Small molecule agonists of neurotensin receptor 1

ABSTRACT

Provided herein are small molecule neurotensin receptor agonists, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/319,329, filed Dec. 15, 2016, which is a U.S. National Stage entry ofInternational Application No. PCT/US2015/037515, filed Jun. 24, 2015,which claims the benefit of U.S. Provisional Patent Application No.62/017,046 entitled “SMALL MOLECULE AGONISTS OF NEUROTENSIN RECEPTOR 1”filed on Jun. 25, 2014, all of which are hereby incorporated byreference in their entirety.

SUMMARY OF THE INVENTION

Described herein are compounds that modulate the activity of theneurotensin 1 receptor (NTR1). The neurotensin 1 receptor is atherapeutic target for the treatment of a variety of diseases orconditions. In some embodiments, the neurotensin 1 receptor is atherapeutic target for the treatment of diseases or conditions such as,but not limited to, neurological diseases or conditions, and cancer. Insome embodiments, the compounds described herein are agonists of theneurotensin 1 receptor.

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, tautomer, or N-oxide thereof:

wherein,

-   -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   A is N or CH;    -   R¹ is halogen, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,        C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ is hydrogen, C₁-C₄alkyl        or C₁-C₄haloalkyl;    -   or    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   and R³ and R⁹ are taken together with the intervening atoms            to form an optionally substituted C₂-C₆heterocycloalkyl;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        —O— or —N(R^(b))—;    -   R² is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,        —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   R⁹ is hydrogen, C₁-C₄alkyl, or C₁-C₄fluoroalkyl;    -   X is —O— or —N(R^(b))—;    -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,        —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   each R^(H) is independently selected from the group consisting        of optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl;    -   n is 1, 2 or 3; and    -   m is 1, 2, 3 or 4.

In another aspect, provided herein is a compound of formula (II), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

-   -   wherein,    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted bicyclic heterocycloalkyl or        an optionally substituted tricyclic heterocycloalkyl;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   or    -   R³ and R⁹ are taken together with the intervening atoms to form        an optionally substituted C₂-C₆heterocycloalkyl;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        —O— or —N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   R⁹ is hydrogen or C₁-C₄alkyl, or C₁-C₄fluoroalkyl;    -   X is —O— or —N(R^(b))—;    -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,        —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or R¹⁰        and R^(b) are taken together with the N atom to which they are        attached to form a C₂-C₆heterocycle;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl;    -   n is 1, 2 or 3; and    -   m is 1, 2, 3 or 4.

In another aspect, provided herein is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

wherein

-   -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   A is N or CH;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        —O— or —N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   L² is absent or an optionally substituted C₁-C₄alkylene;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R¹⁰ and R^(b) are taken together with the N atom to which            they are attached to form a C₂-C₆heterocycle;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl; and    -   m is 1, 2, 3 or 4; and    -   provided that the compound is not        4-(4-(2-(azetidin-1-yl)phenyl)piperazin-1-yl)-2-cyclopropyl-N,N-dimethylquinazolin-6-amine,        4-(4-(2-(azetidin-1-yl)phenyl)piperazin-1-yl)-2-cyclopropyl-N-ethyl-N-methylquinazolin-6-amine,        or        4-(4-(2-(azetidin-1-yl)phenyl)piperidin-1-yl)-2-cyclopropyl-N,N-dimethylquinazolin-6-amine.

In yet another aspect, provided herein is a compound of Formula (IV), ora pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof:

-   -   wherein,    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted bicyclic heterocycloalkyl or        an optionally substituted tricyclic heterocycloalkyl;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        —O— or —N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   L² is absent or an optionally substituted C₁-C₄alkylene;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R¹⁰ and R^(b) are taken together with the N atom to which            they are attached to form a C₂-C₆heterocycle;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl; and    -   m is 1, 2, 3 or 4.

In another aspect, provided herein is a compound of Formula (V), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

-   -   wherein:    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted hetereocycloalkyl, wherein        if ring B is substituted then it is substituted with R⁵ and R⁶;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        —O— or —N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R¹⁰ and R^(b) are taken together with the N atom to which            they are attached to form a C₂-C₆heterocycle;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl; and    -   m is 1, 2, 3 or 4.

In yet another aspect, provided herein is a compound of Formula (VI), ora pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof:

-   -   wherein:    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, or monocyclic        heteroaryl;    -   ring B is an optionally substituted hetereocycloalkyl, wherein        if ring B is substituted then it is substituted with R⁵ and R⁶;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        —O— or —N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   L² is absent or an optionally substituted C₁-C₄alkylene;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R¹⁰ and R^(b) are taken together with the N atom to which            they are attached to form a C₂-C₆heterocycle;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   X is —O— or —N(R^(b))—;    -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,        —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl;    -   n is 1, 2 or 3; and    -   m is 1, 2, 3 or 4.

In another aspect, provided herein is a compound of Formula (VII), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

wherein:

-   -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted hetereocycloalkyl; wherein        if ring B is substituted then it is substituted with R⁵ and R⁶;    -   L³ is absent or an optionally substituted C₁-C₄alkylene;    -   R^(b) is hydrogen, optionally substituted C₁-C₄alkyl, optionally        substituted C₁-C₄haloalkyl, —C(═O)R¹¹, —C(═O)—O—R¹¹, —S(═O)₂R¹¹,        or —C(═O)R¹¹;    -   R^(d) is hydrogen, optionally substituted C₁-C₄alkyl, optionally        substituted C₁-C₄haloalkyl, or optionally substituted        C₁-C₆heterocycloalkyl, wherein if R^(d) is substituted then it        is substituted with R¹;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   or R^(b) and R^(d) taken together with the nitrogen to which        they are attached form an optionally substituted        C₂-C₆heterocycloalkyl;    -   each Y¹, Y², Y³, and Y⁴ is independently selected from N and        CR², provided that at least 1 of Y¹, Y², Y³, and Y⁴ is CR².    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, —N(R³)—R⁴, optionally        substituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy,        optionally substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R^(b) and R¹⁰ are taken together with the nitrogen to which            they are attached form an optionally substituted            C₂-C₆heterocycloalkyl;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   each R^(H) is independently selected from the group consisting        of optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl.

In yet another aspect, provided herein is a compound of Formula (VIII),or a pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof:

-   -   wherein:    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted hetereocycloalkyl;    -   each Y¹, Y², Y³, and Y⁴ is independently selected from N and        CR², provided that at least 1 of Y¹, Y², Y^(d), and Y⁴ is N;    -   G is optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄haloalkyl, -L¹-R^(d), or -L³-N(R^(b))—R^(d);        -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene,            C₁-C₄alkynylene, —O— or —N(R^(b))—;        -   L³ is absent or an optionally substituted C₁-C₄alkylene;        -   R^(b) is hydrogen, optionally substituted C₁-C₄alkyl,            optionally substituted C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R^(d) is hydrogen, optionally substituted C₁-C₄alkyl, optionally        substituted C₁-C₄haloalkyl, or optionally substituted        C₁-C₆heterocycloalkyl, wherein if R^(d) is substituted then it        is substituted with R¹;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;        -   or R^(b) and R^(d) taken together with the nitrogen to which            they are attached form an optionally substituted            C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, —N(R³)—R⁴, optionally        substituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy,        optionally substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R^(b) and R¹⁰ are taken together with the nitrogen to which            they are attached form an optionally substituted            C₂-C₆heterocycloalkyl;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl;    -   provided that the compound is not        2-cyclopropyl-6-methoxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)pyrido[3,4-d]pyrimidine        or        2-cyclopropyl-4-(4-(2-methoxyphenyl)piperazin-1-yl)pyrido[2,3-d]pyrimidine.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound of Formula (I), (II), (III), (IV), (V), (VI),(VII) or (VIII), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In some embodiments, the compound of Formula (I), (II), (III), (IV),(V), (VI), (VII) or (VIII), or a pharmaceutically acceptable saltthereof, is formulated for intravenous injection, subcutaneousinjection, oral administration, inhalation, nasal administration,topical administration, ophthalmic administration or oticadministration. In some embodiments, the compound of Formula (I), (II),(III), (IV), (V), (VI), (VII) or (VIII), or a pharmaceuticallyacceptable salt thereof, is formulated as (i.e. incorporated into) atablet, a pill, a capsule, a liquid, an inhalant, a nasal spraysolution, a suppository, a suspension, a gel, a solution, an ointment, alotion, an eye drop or an ear drop

In another aspect, described herein is a method of treating a disease,disorder or condition mediated by neurotensin and/or neurotensinreceptor 1 in a subject in need thereof, which method comprisesadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII),or a pharmaceutically acceptable salt thereof. In another aspect,described herein is a method of treating a disease in a subject mediatedby neurotensin and/or neurotensin receptor 1, which method comprisesadministering to the subject a pharmaceutical composition comprising acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII),or a pharmaceutically acceptable salt thereof. In some embodiments, thedisease, disorder, condition is drug abuse. In some embodiments, thedisease, disorder or condition is Parkinson's disease. In someembodiments, the disease is schizophrenia. In some embodiments, thedisease, disorder or condition is pain.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the compound of Formula (I), (II), (III),(IV), (V), (VI), (VII) or (VIII), is systemically administered to themammal; and/or (b) the effective amount of the compound is administeredorally to the mammal; and/or (c) the effective amount of the compound isintravenously administered to the mammal; and/or (d) the effectiveamount of the compound is administered by inhalation; and/or (e) theeffective amount of the compound is administered by nasaladministration; or and/or (f) the effective amount of the compound isadministered by injection to the mammal; and/or (g) the effective amountof the compound is administered topically to the mammal; and/or (h) theeffective amount of the compound is administered by ophthalmicadministration; and/or (i) the effective amount of the compound isadministered rectally to the mammal; and/or (j) the effective amount isadminstered non-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In any of the aforementioned aspects involving the administration of acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII),or a pharmaceutically acceptable salt thereof, to a subject are furtherembodiments comprising administering at least one additional agent inaddition to the administration of a compound having the structure ofFormula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), or apharmaceutically acceptable salt thereof. In various embodiments, thecompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII)and the additional agent are administered in any order, includingsimultaneously. In some embodiments, the compound of Formula (I), (II),(III), (IV), (V), (VI), (VII) or (VIII) and the additional agent areadministered to the subject in the same pharmaceutical composition or inseparate pharmaceutical compositions.

In any of the embodiments disclosed herein, the subject is a human.

In some embodiments, compounds and compositions provided herein areadministered to a human.

In some embodiments, compounds and compositions provided herein areorally administered.

In other embodiments, compounds provided herein are used for theformulation of a medicament for the modulation of the activity of theneurotensin 1 receptor in a subject.

Articles of manufacture, which include packaging material, a compound ofFormula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), or apharmaceutically acceptable salt thereof, within the packaging material,and a label that indicates that the compound or composition, orpharmaceutically acceptable salt, tautomers, pharmaceutically acceptableN-oxide, pharmaceutically active metabolite, pharmaceutically acceptableprodrug, or pharmaceutically acceptable solvate thereof, is used for thetreatment of diseases or conditions that would benefit from modulationof the neurotensin 1 receptor, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description

DETAILED DESCRIPTION OF THE INVENTION

Neurotensin is a 13 amino acid neuropeptide that is implicated in theregulation of luteinizing hormone and prolactin release and hassignificant interaction with the dopaminergic system. Neurotensin wasfirst isolated from extracts of bovine hypothalamus based on its abilityto cause a visible vasodilation in the exposed cutaneous regions ofanesthetized rats. Neurotensin is distributed throughout the centralnervous system, with highest levels in the hypothalamus, amygdala andnucleus accumbens. It induces a variety of effects, including:analgesia, hypothermia and increased locomotor activity. It is alsoinvolved in regulation of dopamine pathways. In the periphery,neurotensin is found in endocrine cells of the small intestine, where itleads to secretion and smooth muscle contraction

Neurotensin has been implicated in the modulation of dopamine signaling,and produces a spectrum of pharmacological effects resembling those ofantipsychotic drugs, leading to the suggestion that neurotensin may bean endogenous neuroleptic. Neurotensin-deficient mice display defects inresponses to several antipsychotic drugs consistent with the idea thatneurotensin signaling is a key component underlying at least someantipsychotic drug actions. These mice exhibit modest defects inprepulse inhibition (PPI) of the startle reflex, a model that has beenwidely used to investigate antipsychotic drug action in animals.Antipsychotic drug administration augments PPI under certain conditions.Comparisons between normal and neurotensin-deficient mice revealedstriking differences in the ability of different antipsychotic drugs toaugment PPI. While the atypical antipsychotic drug clozapine augmentedPPI normally in neurotensin-deficient mice, the antipsychotichaloperidol and the antipsychotic quetiapine were ineffective in thesemice, in contrast to normal mice where these drugs significantlyaugmented PPI. These results suggest that certain antipsychotic drugsrequire neurotensin for at least some of their effects.Neurotensin-deficient mice also display defects in striatal activationfollowing haloperidol, but not clozapine administration in comparison tonormal wild type mice, indicating that striatal neurotensin is requiredfor the full spectrum of neuronal responses to a subset of antipsychoticdrugs.

Neurotensin is an endogenous neuropeptide involved in thermoregulationthat can induce hypothermia and neuroprotection in experimental modelsof cerebral ischemia.

The neurotensin receptors are transmembrane receptors that bind theneurotransmitter neurotensin. Two of the receptors encoded by the NTSR1and NTSR2 genes contain seven transmembrane helices and are G proteincoupled. The third receptor has a single transmembrane domain and isencoded by the SORT1gene.

Addiction is the continued repetition of a behavior despite adverseconsequences, or a neurological impairment leading to such behaviors.Addictions can include, but are not limited to, drug abuse, exerciseaddiction, food addiction, sexual addiction, computer addiction andgambling. Classic hallmarks of addiction include impaired control oversubstances or behavior, preoccupation with substance or behavior,continued use despite consequences, and denial. Habits and patternsassociated with addiction are typically characterized by immediategratification (short-term reward), coupled with delayed deleteriouseffects (long-term costs). Some drugs associated with addiction includealcohol, substituted amphetamines (e.g. methamphetamine), barbiturates,benzodiazepines (particularly alprazolam, temazepam, diazepam andclonazepam), cocaine, methaqualone, and opioids.

Neurotensin (NT) receptors are expressed on dopaminergic neurologicalpathways associated with reward, and the neurotensin receptor 1 (NTR1)is a therapeutic target for the treatment of methamphetamine abuse. Inparticular, peptide-based NTR1 agonists produce behaviors that areopposite to the psychostimulant effects observed with psychoactivedrugs, such as but not limited to methamphetamine, such ashyperactivity, neurotoxicity, psychotic episodes, and cognitivedeficits.

NTR1 is a G protein coupled receptor (GPCR). Two distinct,interdependent paradigms are associated with GPCR signaling. In additionto the well-defined signaling cascades involving heterotrimeric Gproteins, recent advances in receptor pharmacology have identified theimportance of β-arrestins in regulating alternative biochemical cascadesthat produce their own unique biological effects. For example, in amouse model, Allen et al developed a series of β-arrestin-2 biasedagonists for the D(2)R with antipsychotic properties, and mostimportantly, a reduced propensity to induce catalepsy like standardneuroleptic antagonists (Allen et al. Discovery of β-Arrestin-BiasedDopamine D2 Ligands for Probing Signal Transduction Pathways Essentialfor Antipsychotic Efficacy. Proc. Natl. Acad. Sci. USA. 2011, 108,18488-18493; Rajagopal et al. Teaching old receptors new tricks: biasingseven-transmembrane receptors. Nat. Rev. Drug Discovery 2010, 9,373-386). Studies with those biased compounds illustrate how liganddirected signaling bias, in this case favoring β-arrestin, canameliorate undesirable biological outcomes. Downstream modulators ofβ-arrestin/GPCR signaling are less characterized than their G proteincounterparts, and, due to their potential as targets for producing newmedical therapies are the subjects of increasing numbers ofinvestigations. Recognized β-arrestin partners include the proteins Src,ERK, and Jnk. Their agonist-induced interactions with β-arrestin areassociated with clathrin-compartmentalized signaling and theaccumulation of ligand activated β-arrestin/GPCR complexes in clathrincoated pits. The determination as to whether a GPCR ligand is biasedtowards or against β-arrestin may consequently be evaluated by followingthese biochemical processes.

In one aspect, compounds described herein are used in the treatment of adisease or condition in a subject that is mediated by neurotensin and/orneurotensin receptor 1.

In one aspect, compounds described herein are used in the treatment of aneurological disease or condition mediated by neurotensin and/orneurotensin receptor 1. In some embodiments, the neurological disease orcondition is acute stress disorder, alcohol abuse, alcohol dependence,alcohol withdrawal, alcoholic hallucinosis, alzheimer's disease,amphetamine dependence, amphetamine withdrawal psychosis, anorexianervosa, anxiety disorder, anxiolytic-related disorders, aspergersyndrome, attention deficit disorder, attention deficit hyperactivitydisorder, autism, barbiturate dependence, benzodiazepine dependence,benzodiazepine misuse, benzodiazepine withdrawal, bipolar disorder,bipolar I disorder, bipolar II disorder, bulimia nervosa, cannabisdependence, catatonic disorder, catatonic schizophrenia, cocainedependence, cocaine intoxication, cotard delusion, cyclothymia, deliriumtremens, depressive disorder, generalized anxiety disorder, grandiosedelusions, hallucinogen-related disorder, hallucinogen persistingperception disorder, huntington's disease, impulse control disorder,intermittent explosive disorder, major depressive disorder, majordepressive episode, manic episode, minor depressive disorder, minordepressive episode, munchausen's syndrome, neuroleptic-related disorder,night eating syndrome, obsessive-compulsive disorder (OCD), opioiddependence, pain disorder, panic disorder, paranoid personalitydisorder, parasomnia, parkinson's disease, partner relational problem,pathological gambling, phencyclidine (or phencyclidine-like)-relateddisorder, residual schizophrenia, sadomasochism, schizoaffectivedisorder, schizoid personality disorder, schizophrenia, schizophreniformdisorder, schizotypal personality disorder, social anxiety disorder,social phobia, substance-related disorder, tardive dyskinesia, ortourette syndrome.

In some embodiments, compounds described herein are useful in thetreatment of amphetamine addiction. In some embodiments, the amphetamineis Methamphetamine, ethylamphetamine, propylamphetamine,isopropylamphetamine, phentermine, phenylpropanolamine (PPA), Cathine,Cathinone, Ortetamine, 2-Fluoroamphetamine (2-FA), 3-Methylamphetamine(3-MA), 3-Fluoroamphetamine (3-FA), Norfenfluramine, 4-Methylamphetamine(4-MA), para-Methoxyamphetamine (PMA), para-Ethoxyamphetamine,4-Methylthioamphetamine (4-MTA), Norpholedrine (α-Me-TRA),para-Bromoamphetamine (PBA, 4-BA), para-Chloroamphetamine (PCA, 4-CA),para-Fluoroamphetamine (PFA, 4-FA, 4-FMP), para-Iodoamphetamine (PIA,4-IA), Dimethylamphetamine, Benzphetamine, Selegiline, Mephentermine,Phenpentermine, Ephedrine (EPH), Pseudoephedrine (PSE), Methcathinone,Ethcathinone, Clortermine, Methoxymethylamphetamine (MMA), Fenfluramine,Dexfenfluramine, 4-Methylmethamphetamine (4-MMA),Para-methoxymethamphetamine (PMMA), para-Methoxyethylamphetamine (PMEA),Pholedrine, Chlorphentermine, para-Fluoromethamphetamine (PFMA, 4-FMA),Xylopropamine, alpha-Methyldopamine (alpha-Me-DA),Methylenedioxyamphetamine (MDA), Dimethoxyamphetamine (DMA), Nordefrin(alpha-Me-NE), Oxilofrine, Aleph, Dimethoxybromoamphetamine (DOB),Dimethoxychloroamphetamine (DOC), Dimethoxyfluoroethylamphetamine(DOEF), Dimethoxyethylamphetamine (DOET), Dimethoxyfluoroamphetamine(DOF), Dimethoxyiodoamphetamine (DOI), Dimethoxymethylamphetamine (DOM),Dimethoxynitroamphetamine (DON), Dimethoxypropylamphetamine (DOPR),Dimethoxytrifluoromethylamphetamine (DOTFM),Methylenedioxymethamphetamine (MDMA), Methylenedioxyethylamphetamine(MDEA), Methylenedioxyhydroxyamphetamine (MDOH), 2-Methyl-MDA,5-Methyl-MDA, Methoxymethylenedioxyamphetamine (MMDA),Trimethoxyamphetamine (TMA), Dimethylcathinone, Diethylcathinone,Bupropion, Mephedrone (4-MMC), Methedrone (PMMC), Brephedrone (4-BMC),Flephedrone (4-FMC). In some embodiments, the amphetamine ismethamphetamine.

In certain instances, compounds described herein are used in thetreatment of stroke/cerebral ischemia. In certain instances, compoundsdescribed herein reduce infarct formation and/or brain cell death. Incertain instances, compounds described herein increase patient recoverypost-stroke.

In a further aspect, compounds described herein are used in thetreatment of neurotensin-dependent pathologies.

In one aspect, compounds described herein are used in the treatment ofneuropsychiatric disorders mediated by neurotensin and/or neurotensinreceptor 1, for example substance abuse, psychosis, schizophrenia,Parkinson's disease, attention deficit hyperactivity disorder (ADHD),and pain. In some embodiments, compounds described herein are used inthe treatment of schizophrenia. In some embodiments, compounds describedherein are used in the treatment of Parkinson's disease. In someembodiments, compounds described herein are used in the treatment ofpain. In some embodiments, the pain is acute pain or chronic pain. Insome embodiments, the pain is neuropathic pain, e.g., chronicneuropathic pain.

In some embodiments, compounds described herein are used in thetreatment of schizophrenia. In some embodiments, the schizophrenia isnewly diagnosed or not adequately controlled or resistant to the typicaland atypical anti-psychotics.

In some embodiments, the neuropsychiatric disorder is substance abuse.In some embodiments, the neuropsychiatric disorder is substance abuseand the substance of abuse is, for example an opiate (e.g., heroin,morphine, codeine), a psychomotor stimulant (e.g., amphetamine,methamphetamine (meth), ephedrine, or pseudoephedrine), a cannabinoids(e.g., tetrahydrocannabinol (THC)), alcohol, nicotine, or ahallucinogen. In some embodiments, compounds described herein are usedin the treatment of alcohol addiction in subjects that have failednon-pharmacologic intervention. In some embodiments, compounds describedherein are used in the treatment of psychostimulant addiction insubjects that have failed non-pharmacologic intervention.

In some embodiments, the neuropsychiatric disorder is an eating disordersuch as bulimia nervosa, binge eating disorder, compulsive overeating,anxiety, sleep disorder, or bipolar disorder. In some embodiments,compounds described herein are used to reduce food intake and/orincrease satiety.

In one other aspect compounds described herein are used in the treatmentof a neurodegenerative disease mediated by neurotensin and/orneurotensin receptor 1, for example, Alzheimer's disease, Hungtinton'sdisease, or Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease).In some embodiments, compounds described herein are used in thetreatment of a neurodegenerative disease, wherein the compound describedherein alleviates one or more symptoms or side effects of theneurodegenerative disease. In some embodiments the symptoms or sideeffects of neurodegenerative diseases include, but are not limited to,dementia, memory loss, dyskinesias, cognitive impairment, tremors,rigidity, slowness of movement, postural instability, involuntaryjerking or writhing movements (chorea), slow or abnormal eye movements,difficulty with the physical production of speech or swallowing,psychiatric disorders, muscle cramps and spasms, spasticity,constipation, fatigue, excessive salivation, excessive phlegm, pain,sleep problems, uncontrolled outbursts of laughing or crying.

In one other aspect, compounds described herein are used in thetreatment of cancer. In some embodiments, the cancer is a solid tumor.In some embodiments, the cancer is bladder cancer, colon cancer, braincancer, breast cancer, bone cancer, endometrial cancer, heart cancer,kidney cancer, lung cancer, liver cancer, uterine cancer, ovariancancer, pancreatic cancer, prostate cancer, thyroid cancer, or skincancer

In one other aspect, compounds described herein are used in thetreatment of cardiovascular disorders such as, but not limited to,hypertension, coronary artery disease, cardiomyopathy, or inflammatoryheart disease.

Compounds

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, tautomer, or N-oxide thereof:

-   -   wherein,    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl; A is N or CH;    -   R¹ is halogen, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,        C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ is hydrogen, C₁-C₄alkyl        or C₁-C₄haloalkyl;    -   or    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ and R⁹        are taken together with the intervening atoms to form an        optionally substituted C₂-C₆heterocycloalkyl;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        or N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   R⁹ is hydrogen, C₁-C₄alkyl, or C₁-C₄fluoroalkyl;    -   X is —O— or —N(R^(b))—;    -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,        —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   each R^(H) is independently selected from the group consisting        of optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl;    -   n is 1, 2 or 3; and    -   m is 1, 2, 3 or 4.

Any combination of the groups described above or below for the variousvariables is contemplated herein. For example, in some embodiments ringA is monocyclic heteroaryl. In some embodiments ring A is a monocyclic 6membered heteroaryl. In some embodiments ring A is a monocyclic 5membered heteroaryl. In some embodiments ring A is pyridine, pyrimidine,pyrazine, pyridazine, or thiophene. In some embodiments ring A ispyridine. In some embodiments ring A is thiophene. In some otherembodiments, ring A is C₃-C₆cycloalkyl or phenyl. In some otherembodiments, ring A is C₃-C₆cycloalkyl. In some embodiment ring A iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Insome embodiments ring A is cyclopentyl. In some other embodiments, ringA is phenyl.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure:

In some embodiments, L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene,C₁-C₄alkynylene, or N(R^(b))—. In some embodiments, L¹ is absent,C₁-C₄alkylene, C₁-C₄alkenylene, or C₁-C₄alkynylene. In some embodiments,L¹ is C₁-C₄alkylene. In some embodiments, L¹ is C₁-C₄alkenylene. In someembodiments, L¹ is C₁-C₄alkynylene. In some embodiments, L¹ is —O— orN(R^(b))—. In some embodiments, L¹ is N(R^(b))—. In some embodiments, L¹is —O—.

In some embodiments, L¹ is absent.

In some embodiments R² is hydrogen, halogen, —CN, —OH, —NO₂, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionallysubstituted C₁-C₄haloalkyl. In some embodiments R² is hydrogen, halogen,or methyl.

In some embodiments The compound of claim 4 or claim 5, n the compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, prodrug,or N-oxide thereof has the following structure of Formula (Ia):

In some embodiments R¹ is halogen, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ is hydrogen, orC₁-C₄alkyl.

In some embodiments R¹ is F, C₁-C₄alkyl, or C₁-C₄fluoroalkyl. In someembodiments R¹ is F or C₁-C₄fluoroalkyl. In some embodiments R¹ is F. Insome embodiments R¹ is methyl. In some embodiments R¹ is CF₃.

In some embodiments R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ and R⁹ are takentogether with the intervening atoms to form an optionally substitutedC₂-C₆heterocycloalkyl.

In some embodiments R³ and R⁹ are taken together with the interveningatoms to form an optionally substituted C₂-C₆heterocycloalkyl, whereinthe optionally substituted C₂-C₆heterocycloalkyl is an optionallysubstituted azetidenyl, optionally substituted pyrrolidinyl, oroptionally substituted piperidinyl. In some embodiments the optionallysubstituted C₂-C₆heterocycloalkyl is optionally substitutedpyrrolidinyl.

In some embodiments R¹ is hydrogen, F, C₁-C₄alkyl, or C₁-C₄fluoroalkyl.In some embodiments R¹ is hydrogen, methyl, or CF₃ and R³ and R⁹ aretaken together with the intervening atoms to form an optionallysubstituted C₂-C₆heterocycloalkyl.

In some embodiments the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure of Formula (Ib):

In some embodiments, the compound of Formula (Ib) has one of thefollowing structures:

In some embodiments A is CH.

In some embodiments A is N.

In some embodiments, m is 1 or 2. In some embodiments, m is 1. In someembodiments, m is 2.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, X is O. In some embodiments X—N(R^(b))—. In someembodiments X is NH.

In some embodiments R¹⁰ is hydrogen, or C₁-C₄alkyl. In some embodimentsR¹⁰ is hydrogen.

In some embodiments R⁸ is C₁-C₄alkoxy, or —N(R^(a))₂. In someembodiments R⁸ is methoxy. In some embodiments R⁸ is —N(R^(a))₂. In someembodiments R⁸ is —N(R^(a))₂ where —N(R^(a))₂ is dimethylamino orazetidenyl.

In some embodiments R⁷ is hydrogen, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy. In some embodiments R⁷is hydrogen or halogen. In some embodiments R⁷ is hydrogen.

In another aspect, provided herein is a compound of formula (II), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

-   -   wherein,    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted bicyclic heterocycloalkyl or        an optionally substituted tricyclic heterocycloalkyl;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   or    -   R³ and R⁹ are taken together with the intervening atoms to form        an optionally substituted C₂-C₆heterocycloalkyl;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        or N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   R⁹ is hydrogen or C₁-C₄alkyl, or C₁-C₄fluoroalkyl;    -   X is —O— or —N(R^(b))—;    -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,        —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or R¹⁰        and R^(b) are taken together with the N atom to which they are        attached to form a C₂-C₆heterocycle;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl;    -   n is 1, 2 or 3; and    -   m is 1, 2, 3 or 4.

In some embodiments ring A is monocyclic heteroaryl. In some embodimentsring A is monocyclic 6-membered heteroaryl. In some embodiments ring Ais monocyclic 5-membered heteroaryl. In some embodiments ring A ispyridine, pyrimidine, pyrazine, pyridazine, or thiophene. In someembodiments ring A is pyridine. In some embodiments ring A is thiophene.

In some embodiments, ring A is C₃-C₆cycloalkyl or phenyl. In someembodiments, ring A is phenyl.

In some embodiments, ring A is C₃-C₆cycloalkyl. In some embodiment ringA is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.In some embodiments ring A is cyclopentyl.

In some embodiments, the compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure:

In some embodiments L¹ is absent.

In some embodiments R² is hydrogen, halogen, —CN, —OH, —NO₂, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionallysubstituted C₁-C₄haloalkyl. In some embodiments R² is hydrogen, halogen,or methyl.

In some embodiments, the compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure of Formula (Ha):

In some embodiments R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ is hydrogen, orC₁-C₄alkyl. In some embodiments R¹ is F or C₁-C₄haloalkyl. In someembodiments R¹ is hydrogen, F, C₁-C₄alkyl, or C₁-C₄fluoroalkyl. In someembodiments R¹ is methyl or CF₃.

In some embodiments R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ and R⁹ are takentogether with the intervening atoms to form an optionally substitutedC₂-C₆heterocycloalkyl.

In some embodiments R¹ is hydrogen, F, C₁-C₄alkyl, or C₁-C₄fluoroalkyl;and R³ and R⁹ are taken together with the intervening atoms to form anoptionally substituted C₂-C₆heterocycloalkyl. In some embodiments R³ andR⁹ are taken together with the intervening atoms to form an optionallysubstituted C₂-C₆heterocycloalkyl, wherein the optionally substitutedC₂-C₆heterocycloalkyl is optionally substituted azetidenyl, optionallysubstituted pyrrolidinyl, or optionally substituted piperidinyl. In someembodiments the optionally substituted C₂-C₆heterocycloalkyl isoptionally substituted pyrrolidinyl.

In some embodiments R¹ is methyl or CF₃.

In some embodiments, the compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure of Formula (IIb):

In some embodiments, the compound of Formula (IIb) has one of thefollowing structures:

In some embodiments m is 1 or 2. In some embodiments m is 1. In someembodiments m is 2.

In some embodiments n is 1 or 2. In some embodiments n is 1. In someembodiments n is 2.

In some embodiments X is O. In some embodiments X is N(R^(b))—. In someembodiments X is NH.

In some embodiments R¹⁰ is hydrogen, or C₁-C₄alkyl. In some embodiments,R¹⁰ is hydrogen.

In some embodiments R⁸ is C₁-C₄alkoxy, or —N(R^(a))₂. In someembodiments R⁸ is methoxy. In some embodiments R⁸ is —N(R^(a))₂. In someembodiments R⁸ is —N(R^(a))₂, where —N(R^(a))₂ is dimethylamino. In someembodiments R⁸ is —N(R^(a))₂, where —N(R^(a))₂ is azetidenyl.

In some embodiments R⁷ is hydrogen, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy. In some embodiments R⁷is hydrogen or halogen. In some embodiments R⁷ is hydrogen.

In some embodiments ring B is an N-containing optionally substitutedbicyclic heterocycloalkyl. In some embodiments ring B is an N-containingoptionally substituted bicyclic heterocycloalkyl, wherein N-containingoptionally substituted bicyclic heterocycloalkyl isoctahydropyrrolo[3,4-c]pyrrolyl, decahydro-2,6-naphthyridinyl,decahydro-2,7-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, or2,6-diazaspiro[3.3]heptanyl.

In some embodiments ring B is an N-containing optionally substitutedtricyclic heterocycloalkyl.

In some embodiments ring B is

In another aspect, provided herein is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

wherein

-   -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   A is N or CH;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        or —N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   L² is absent or an optionally substituted C₁-C₄alkylene;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R¹⁰ and R^(b) are taken together with the N atom to which            they are attached to form a C₂-C₆heterocycle;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl; and    -   m is 1, 2, 3 or 4; and    -   provided that the compound is not        4-(4-(2-(azetidin-1-yl)phenyl)piperazin-1-yl)-2-cyclopropyl-N,N-dimethylquinazolin-6-amine,        4-(4-(2-(azetidin-1-yl)phenyl)piperazin-1-yl)-2-cyclopropyl-N-ethyl-N-methylquinazolin-6-amine,        or        4-(4-(2-(azetidin-1-yl)phenyl)piperidin-1-yl)-2-cyclopropyl-N,N-dimethylquinazolin-6-amine.

In some embodiments ring A is monocyclic heteroaryl. In some embodimentsring A is pyridine, pyrimidine, pyrazine, pyridazine, or thiophene. Insome embodiments ring A is pyridine. In some embodiments ring A isthiophene.

In some embodiments ring A is C₃-C₆cycloalkyl or phenyl. In someembodiments ring A phenyl.

In some embodiments ring A is C₃-C₆cycloalkyl. In some embodiment ring Ais cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Insome embodiments ring A is cyclopentyl.

In some embodiments the compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure:

In some embodiments L¹ is absent; and L² is absent.

In some embodiments R² is hydrogen, halogen, —CN, —OH, —NO₂, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionallysubstituted C₁-C₄haloalkyl. In some embodiments R² is hydrogen, halogen,or methyl.

In some embodiments Formula (III), or a pharmaceutically acceptablesalt, solvate, prodrug, or N-oxide thereof has the following structureof Formula (Ma):

In some embodiments R³ is hydrogen or C₁-C₄alkyl; and R⁴ is C₁-C₄ alkyl,C₁-C₄ alkylene-OR¹⁰, or C₁-C₄ alkylene-N(R^(b))(R¹⁰). In someembodiments R¹⁰ and R^(b) are taken together with the N atom to whichthey are attached to form a C₂-C₆heterocycle. In some embodiments R¹⁰and R^(b) are taken together with the N atom to which they are attachedto form a C₂-C₆heterocycle, where the C₂-C₆heterocycle is a 5 or 6membered heterocycle. In some embodiments R¹⁰ and R^(b) are takentogether with the N atom to which they are attached to form aC₂-C₆heterocycle, where the C₂-C₆heterocycle is pyrrolidinyl,piperidinyl, or morpholinyl.

In some embodiments R³ and R⁴ taken together with the nitrogen to whichthey are attached form an optionally substituted C₂-C₅heterocycloalkyl.In some embodiments R³ and R⁴ taken together with the nitrogen to whichthey are attached form an optionally substituted C₂-C₅heterocycloalkyl,wherein the optionally substituted C₂-C₅heterocycloalkyl is optionallysubstituted azetidenyl, optionally substituted pyrrolidinyl, oroptionally substituted piperidinyl. In some embodiments the optionallysubstituted C₂-C₅heterocycloalkyl is optionally substitutedpyrrolidinyl.

In some embodiments A is CH.

In some embodiments A is N.

In some embodiments R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,or —N(R^(a))₂.

In some embodiments m is 1 or 2.

In some embodiments each R^(a) is independently selected from a groupconsisting of hydrogen and C₁-C₄ alkyl; or 2 R^(a) taken together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₄heterocycloalkyl.

In some embodiments each R^(a) is methyl. In some embodiments 2 R^(a)taken together with the nitrogen to which they are attached form anazeridinyl or azetidinyl ring.

In some embodiments R⁷ is hydrogen, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy.

In yet another aspect, provided herein is a compound of Formula (IV), ora pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof:

-   -   wherein,    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted bicyclic heterocycloalkyl or        an optionally substituted tricyclic heterocycloalkyl;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        or N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   L² is absent or an optionally substituted C₁-C₄alkylene;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R¹⁰ and R^(b) are taken together with the N atom to which            they are attached to form a C₂-C₆heterocycle;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl; and    -   m is 1, 2, 3 or 4.

In some embodiments ring A is monocyclic heteroaryl. In some embodimentsring A is pyridine, pyrimidine, pyrazine, pyridazine, or thiophene. Insome embodiments ring A is pyridine. In some embodiments ring A isthiophene.

In some ring A is C₃-C₆cycloalkyl or phenyl.

In some embodiment ring A is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl. In some embodiments ring A is cyclopentyl.

In some embodiments the compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure:

In some embodiments L¹ is absent; and L² is absent.

In some embodiments R² is hydrogen, halogen, —CN, —OH, —NO₂, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionallysubstituted C₁-C₄haloalkyl. In some embodiments R² is hydrogen, halogen,or methyl.

In some embodiments the compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure of Formula (IVa):

In some embodiments R³ is hydrogen or C₁-C₄alkyl; and R⁴ is C₁-C₄ alkyl,C₁-C₄ alkylene-OR¹⁰, or C₁-C₄ alkylene-N(R^(b))(R¹⁰). In someembodiments R¹⁰ and R^(b) are taken together with the N atom to whichthey are attached to form a C₂-C₆heterocycle. In some embodiments theC₂-C₆heterocycle is pyrrolidinyl, piperidinyl, or morpholinyl.

In some embodiments R³ and R⁴ taken together with the nitrogen to whichthey are attached form an optionally substituted C₂-C₅heterocycloalkyl;

In some embodiments the optionally substituted C₂-C₅heterocycloalkyl isoptionally substituted azetidenyl, optionally substituted pyrrolidinyl,or optionally substituted piperidinyl. In some embodiments theoptionally substituted C₂-C₅heterocycloalkyl is optionally substitutedpyrrolidinyl.

In some embodiments R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,or —N(R^(a))₂.

In some embodiments m is 1 or 2.

In some embodiments each R^(a) is independently selected from a groupconsisting of hydrogen and C₁-C₄ alkyl; or 2 R^(a) taken together withthe nitrogen to which they are attached form an optionally substitutedC₂-C₄heterocycloalkyl.

In some embodiments each R^(a) is methyl. In some embodiments 2 R^(a)taken together with the nitrogen to which they are attached form anazeridinyl or azetidinyl ring.

In some embodiments R⁷ is hydrogen, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy. In some embodiments R⁷is hydrogen or halogen. In some embodiments R⁷ is hydrogen.

In some embodiments ring B is an N-containing optionally substitutedbicyclic heterocycloalkyl or an N-containing optionally substitutedtricyclic heterocycloalkyl. In some embodiments ring B is anN-containing optionally substituted bicyclic heterocycloalkyl or anN-containing optionally substituted tricyclic heterocycloalkyl, whereinthe N-containing optionally substituted bicyclic heterocycloalkyl or anN-containing optionally substituted tricyclic heterocycloalkyl isoctahydropyrrolo[3,4-c]pyrrolyl, decahydro-2,6-naphthyridinyl,decahydro-2,7-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, or2,6-diazaspiro[3.3]heptanyl.

In some embodiments ring B is

In another aspect, provided herein is a compound of Formula (V), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

-   -   wherein:    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted hetereocycloalkyl, wherein        if ring B is substituted then it is substituted with R⁵ and R⁶;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        or N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R¹⁰ and R^(b) are taken together with the N atom to which            they are attached to form a C₂-C₆heterocycle;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl; and    -   m is 1, 2, 3 or 4.

In some embodiments ring A is C₃-C₆cycloalkyl, or phenyl. In someembodiments ring A is phenyl. In some embodiments ring A isC₃-C₆cycloalkyl. In some embodiment ring A is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments ring A iscyclopentyl.

In some embodiments ring A is monocyclic heteroaryl. In some embodimentsring A is pyridine, pyrimidine, pyrazine, pyridazine, or thiophene. Insome embodiments ring A is pyridine. In some embodiments ring A isthiophene.

In some embodiments the compound of Formula (V), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure:

In some embodiments L¹ is absent.

In some embodiments R² is hydrogen, halogen, —CN, —OH, —NO₂, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionallysubstituted C₁-C₄haloalkyl. In some embodiments R² is hydrogen, halogen,or methyl.

In some embodiments the compound of Formula (V), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure of Formula (Va):

In some embodiments R³ is hydrogen or C₁-C₄alkyl; and R⁴ is optionallysubstituted C₁-C₄ alkyl, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄alkylene-N(R^(b))(R¹⁰). In some embodiments R¹⁰ and R^(b) are takentogether with the N atom to which they are attached to form aC₂-C₆heterocycle. In some embodiments the C₂-C₆heterocycle ispyrrolidinyl, piperidinyl, or morpholinyl.

In some embodiments R³ and R⁴ taken together with the nitrogen to whichthey are attached form an optionally substituted C₂-C₅heterocycloalkyl;

In some embodiments the optionally substituted C₂-C₅heterocycloalkyl isoptionally substituted azetidenyl, optionally substituted pyrrolidinyl,or optionally substituted piperidinyl. In some embodiments theoptionally substituted C₂-C₅heterocycloalkyl is optionally substitutedpyrrolidinyl.

In some embodiments ring B is an N-containing optionally substitutedmonocyclic heterocycloalkyl.

In some embodiments ring B is

andR⁵ and R⁶ are each independently selected from hydrogen, halogen, —OH,and C₁-C₄alkyl, or when on the same carbon, R⁵ and R⁶ are taken togetherform an oxo. In some embodiments R⁵ and R⁶ are each hydrogen.

In some embodiments ring B is an N-containing optionally substitutedbicyclic heterocycloalkyl or an N-containing optionally substitutedtricyclic heterocycloalkyl. In some embodiments ring B is anN-containing optionally substituted bicyclic heterocycloalkyl or anN-containing optionally substituted tricyclic heterocycloalkyl, whereinthe N-containing optionally substituted bicyclic heterocycloalkyl or anN-containing optionally substituted tricyclic heterocycloalkyl isoctahydropyrrolo[3,4-c]pyrrolyl, decahydro-2,6-naphthyridinyl,decahydro-2,7-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, or2,6-diazaspiro[3.3]heptanyl.

In some embodiments ring B is

In some embodiments R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,or —N(R^(a))₂.

In some embodiments m is 1 or 2.

In some embodiments R⁸ is C₁-C₄alkoxy, or —N(R^(a))₂. In someembodiments the C₁-C₄alkoxy is methoxy. In some embodiments the—N(R^(a))₂ is dimethylamino. In some embodiments the —N(R^(a))₂ isazetidenyl.

In some embodiments R⁷ is hydrogen, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy. In some embodiments R⁷is hydrogen or halogen. In some embodiments R⁷ is hydrogen.

In yet another aspect, provided herein is a compound of Formula (VI), ora pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof:

-   -   wherein,    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, or monocyclic        heteroaryl;    -   ring B is an optionally substituted hetereocycloalkyl, wherein        if ring B is substituted then it is substituted with R⁵ and R⁶;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene, C₁-C₄alkynylene,        or —N(R^(b))—;        -   R^(b) is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   L² is absent or an optionally substituted C₁-C₄alkylene;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R¹⁰ and R^(b) are taken together with the N atom to which            they are attached to form a C₂-C₆heterocycle;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   X is —O— or —N(R^(b))—;    -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,        —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   each R^(H) is independently selected from the group consisting        of optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl;    -   n is 1, 2 or 3; and    -   m is 1, 2, 3 or 4.

In some embodiments ring A is C₃-C₆cycloalkyl. In some embodiment ring Ais cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Insome embodiments ring A is cyclopentyl.

In some embodiments ring A is monocyclic heteroaryl. In some embodimentsring A is monocyclic 5 membered or 6 membered heteroaryl. In someembodiments ring A is monocyclic 5 membered heteroaryl. In someembodiments ring A is monocyclic 6 membered heteroaryl.

In some embodiments ring A is pyridine, pyrimidine, pyrazine,pyridazine, or thiophene. In some embodiments ring A is pyridine. Insome embodiments ring A is thiophene.

In some embodiments L¹ is absent; and L² is absent or —CH₂—.

In some embodiments R² is hydrogen, halogen, —CN, —OH, —NO₂, optionallysubstituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionallysubstituted C₁-C₄haloalkyl. In some embodiments R² is hydrogen, halogen,or methyl.

In some embodiments R³ is hydrogen or C₁-C₄alkyl; and R⁴ is C₁-C₄ alkyl,—C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄ alkylene-N(R^(b))(R¹⁰). In someembodiments R¹⁰ and R^(b) are taken together with the N atom to whichthey are attached to form a C₂-C₆heterocycle. In some embodiments theC₂-C₆heterocycle is pyrrolidinyl, piperidinyl, or morpholinyl.

In some embodiments R³ and R⁴ taken together with the nitrogen to whichthey are attached form an optionally substituted C₂-C₅heterocycloalkyl.

In some embodiments the optionally substituted C₂-C₅heterocycloalkyl isoptionally substituted azetidenyl, optionally substituted pyrrolidinyl,or optionally substituted piperidinyl. In some embodiments theoptionally substituted C₂-C₅heterocycloalkyl is optionally substitutedpyrrolidinyl.

In some embodiments R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,or —N(R^(a))₂. In some embodiment R¹ is hydrogen. In some embodiments R¹is methyl. R¹ is F. R¹ is CF₃.

In some embodiments m is 1 or 2.

In some embodiments R⁷ is hydrogen, halogen, —CN, —OH, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy. In some embodiments R⁷is hydrogen or halogen. R⁷ is hydrogen.

In some embodiments ring B is an N-containing optionally substitutedmonocyclic heterocycloalkyl.

In some embodiments ring B is

andR⁵ and R⁶ are each independently selected from hydrogen, halogen, —OH,and C₁-C₄alkyl, or when on the same carbon, R⁵ and R⁶ are taken togetherform an oxo. In some embodiments R⁵ and R⁶ are each hydrogen.

In some embodiments ring B is an N-containing optionally substitutedbicyclic heterocycloalkyl or an N-containing optionally substitutedtricyclic heterocycloalkyl.

In some embodiments the N-containing optionally substituted bicyclicheterocycloalkyl is octahydropyrrolo[3,4-c]pyrrolyl,decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl,octahydro-1H-pyrrolo[3,4-c]pyridinyl, or 2,6-diazaspiro[3.3]heptanyl.

In some embodiments ring B is

In another aspect, provided herein is a compound of Formula (VII), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

wherein:

-   -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted hetereocycloalkyl; wherein        if ring B is substituted then it is substituted with R⁵ and R⁶;    -   L³ is absent or an optionally substituted C₁-C₄alkylene;    -   R^(b) is hydrogen, optionally substituted C₁-C₄alkyl, optionally        substituted C₁-C₄haloalkyl, —C(═O)R¹¹, —C(═O)—O—R¹¹, —S(═O)₂R¹¹,        or —C(═O)R¹¹;    -   R^(d) is hydrogen, optionally substituted C₁-C₄alkyl, optionally        substituted C₁-C₄haloalkyl, or optionally substituted        C₁-C₆heterocycloalkyl, wherein if R^(d) is substituted then it        is substituted with R¹;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   or R^(b) and R^(d) taken together with the nitrogen to which        they are attached form an optionally substituted        C₂-C₆heterocycloalkyl;    -   each Y¹, Y², Y³, and Y⁴ is independently selected from N and        CR², provided that at least 1 of Y¹, Y², Y³, and Y⁴ is CR².    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, —N(R³)—R⁴, optionally        substituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy,        optionally substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R^(b) and R¹⁰ are taken together with the nitrogen to which            they are attached form an optionally substituted            C₂-C₆heterocycloalkyl;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁵ and R⁶ are each independently selected from hydrogen,        halogen, —OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and        R⁶ are taken together form an oxo;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;    -   each R¹¹ is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl.

In some embodiments ring A is C₃-C₆cycloalkyl or phenyl.

In some embodiment ring A is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl. In some embodiments ring A is cyclopentyl.

In some embodiments ring A is monocyclic heteroaryl. In some embodimentsring A is pyridine, pyrimidine, pyrazine, pyridazine, or thiophene. Insome embodiments ring A is pyridine. In some embodiments ring A isthiophene.

In some embodiments the compound of Formula (VII), or a pharmaceuticallyacceptable salt, solvate, prodrug, or N-oxide thereof has the followingstructure of Formula (VIIa):

In some embodiments Y¹ is N. In some embodiments Y² is N. In someembodiments Y⁴ is N.

In some embodiments R² is —N(R³)—R⁴; and Y² is CH.

In some embodiments Y² is CR²; and each R² is independently selectedfrom a group consisting of hydrogen and optionally substitutedC₁-C₄alkoxy. In some embodiments the optionally substituted C₁-C₄alkoxyis methoxy.

In some embodiments ring B is an N-containing optionally substitutedmonocyclic heterocycloalkyl.

In some embodiments ring B is

andR⁵ and R⁶ are each independently selected from hydrogen, halogen, —OH,and C₁-C₄alkyl, or when on the same carbon, R⁵ and R⁶ are taken togetherform an oxo. In some embodiments R⁵ and R⁶ are each hydrogen.

In some embodiments ring B is an N-containing optionally substitutedbicyclic heterocycloalkyl or an N-containing optionally substitutedtricyclic heterocycloalkyl. In some embodiments ring B is anN-containing optionally substituted bicyclic heterocycloalkyl or anN-containing optionally substituted tricyclic heterocycloalkyl, whereinthe N-containing optionally substituted bicyclic heterocycloalkyl or anN-containing optionally substituted tricyclic heterocycloalkyl isoctahydropyrrolo[3,4-c]pyrrolyl, decahydro-2,6-naphthyridinyl,decahydro-2,7-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, or2,6-diazaspiro[3.3]heptanyl.

In some embodiments ring B is

In some embodiments R^(b) is hydrogen or optionally substitutedC₁-C₄alkyl; and R^(d) is optionally substituted C₁-C₄alkyl or optionallysubstituted C₁-C₆heterocycloalkyl; or R^(b) and R^(d) taken togetherwith the nitrogen to which they are attached form an optionallysubstituted C₂-C₅heterocycloalkyl. In some embodiments the optionallysubstituted C₂-C₅heterocycle is optionally substituted pyrrolidinyl,piperidinyl, or morpholinyl.

In some embodiments R⁸ is C₁-C₄alkoxy, or —N(R^(a))₂; and R⁷ ishydrogen, halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, orC₁-C₄haloalkoxy. In some embodiments R⁸ is methoxy or —N(R^(a))_(z). Insome embodiments —N(R^(a))₂ is dimethylamino, azeridinyl, or azetidinyl.In some embodiments —N(R^(a))₂ is dimethylamino. In some embodiments—N(R^(a))₂ is azetidinyl.

In yet another aspect, provided herein is a compound of Formula (VIII),or a pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof:

-   -   wherein:    -   ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, phenyl or        monocyclic heteroaryl;    -   ring B is an optionally substituted hetereocycloalkyl;    -   each Y¹, Y², Y³, and Y⁴ is independently selected from N and        CR², provided that at least 1 of Y¹, Y², Y^(d), and Y⁴ is N;    -   G is optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄haloalkyl, -L¹-R^(d), or -L³-N(R^(b))—R^(d);        -   L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene,            C₁-C₄alkynylene, or —N(R^(b))—;        -   L³ is absent or an optionally substituted C₁-C₄alkylene;        -   R^(b) is hydrogen, optionally substituted C₁-C₄alkyl,            optionally substituted C₁-C₄haloalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹;    -   R^(d) is hydrogen, optionally substituted C₁-C₄alkyl, optionally        substituted C₁-C₄haloalkyl, or optionally substituted        C₁-C₆heterocycloalkyl, wherein if R^(d) is substituted then it        is substituted with R¹;    -   R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;        -   or R^(b) and R^(d) taken together with the nitrogen to which            they are attached form an optionally substituted            C₂-C₆heterocycloalkyl;    -   R² is hydrogen, halogen, —CN, —OH, —NO₂, —N(R³)—R⁴, optionally        substituted C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy,        optionally substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   R³ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;    -   R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄        alkylene-C(═O)OR¹¹, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄        alkylene-N(R^(b))(R¹⁰);        -   R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; or            R^(b) and R¹⁰ are taken together with the nitrogen to which            they are attached form an optionally substituted            C₂-C₆heterocycloalkyl;    -   or R³ and R⁴ taken together with the nitrogen to which they are        attached form an optionally substituted C₂-C₆heterocycloalkyl;    -   R⁷ is hydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³,        —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —O—C(═O)—R¹¹,        —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹, —N(R¹²)S(═O)₂R¹¹,        —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substituted        C₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally        substituted C₁-C₄haloalkyl, optionally substituted        C₁-C₄haloalkoxy, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, optionally substituted 5- or 6-membered        heteroaryl;    -   R⁸ is hydrogen, —OH, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy,        C₁-C₄fluoroalkoxy, or —N(R^(a))₂;        -   each R^(a) is independently selected from the group            consisting of hydrogen and C₁-C₄ alkyl, —C(═O)R¹¹,            —C(═O)—O—R¹¹, —S(═O)₂R¹¹, —C(═O)R¹¹, or 2 R^(a) taken            together with the nitrogen to which they are attached form            an optionally substituted C₂-C₆heterocycloalkyl;    -   each is independently selected from the group consisting of        optionally substituted C₁-C₄alkyl, optionally substituted        C₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl,        optionally substituted C₂-C₆heterocycloalkyl, optionally        substituted phenyl, and optionally substituted 5- or 6-membered        heteroaryl;    -   each of R¹² and R¹³ is independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₄alkyl,        optionally substituted C₁-C₄fluoroalkyl, optionally substituted        C₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,        optionally substituted phenyl, and optionally substituted 5- or        6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen        atom, are taken together with the nitrogen atom to which they        are attached to form an optionally substituted        C₂-C₆heterocycloalkyl;    -   provided that the compound is not        2-cyclopropyl-6-methoxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)pyrido[3,4-d]pyrimidine        or        2-cyclopropyl-4-(4-(2-methoxyphenyl)piperazin-1-yl)pyrido[2,3-d]pyrimidine.

In some embodiments ring A is C₃-C₆cycloalkyl or phenyl.

In some embodiment ring A is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, or cycloheptyl. In some embodiments ring A is cyclopentyl.

In some embodiments the compound of Formula (VIII), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereofhas the following structure:

In some embodiments ring A is monocyclic heteroaryl.

In some embodiments ring A is pyridine, pyrimidine, pyrazine,pyridazine, or thiophene. In some embodiments ring A is pyridine. Insome embodiments ring A is thiophene.

In some embodiments Y¹ is N. In some embodiments Y² is N. In someembodiments Y³ is N. In some embodiments Y⁴ is N.

In some embodiments the compound of Formula (VIII), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereofhas the following structure of Formula (Villa):

In some embodiments Y² is N; R² is —N(R³)—R⁴; R³ is hydrogen orC₁-C₄alkyl; R⁴ is hydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄alkylene-OR¹⁰, or —C₁-C₄ alkylene-N(R^(b))(e)_(; and R)E)_(is) hydrogen,C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)R¹¹, —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³,—S(═O)₂R¹¹, or —C(═O)R¹¹; or R^(b) and R¹⁰ are taken together with thenitrogen to which they are attached form an optionally substitutedC₂-C₆heterocycloalkyl. In some embodiments R^(b) and R¹⁰ are takentogether with the nitrogen to which they are attached form an optionallysubstituted C₂-C₆heterocycloalkyl, wherein the optionally substitutedC₂-C₆heterocycloalkyl is optionally substituted pyrrolidinyl,piperidinyl, or morpholinyl.

In some embodiments Y² is N; R² is —N(R³)—R⁴; and R³ and R⁴ takentogether with the nitrogen to which they are attached form an optionallysubstituted C₂-C₆heterocycloalkyl.

In some embodiments the optionally substituted C₂-C₆heterocycloalkyl isoptionally substituted azetidenyl, optionally substituted pyrrolidinyl,or optionally substituted piperidinyl. In some embodiments theoptionally substituted C₂-C₆heterocycloalkyl is optionally substitutedpyrrolidinyl.

In some embodiments Y² is CR²; and each R² is independently selectedfrom the group consisting of hydrogen and optionally substitutedC₁-C₄alkoxy. In some embodiments the optionally substituted C₁-C₄alkoxyis methoxy.

In some embodiments ring B is an N-containing optionally substitutedmonocyclic heterocycloalkyl.

In some embodiments ring B is

and R⁵ and R⁶ are each independently selected from hydrogen, halogen,—OH, and C₁-C₄alkyl, or when on the same carbon, R⁵ and R⁶ are takentogether form an oxo.

In some embodiments R⁵ and R⁶ are each hydrogen.

In some embodiments ring B is an N-containing optionally substitutedbicyclic heterocycloalkyl or an N-containing optionally substitutedtricyclic heterocycloalkyl. In some embodiments ring B is anN-containing optionally substituted bicyclic heterocycloalkyl or anN-containing optionally substituted tricyclic heterocycloalkyl, whereinthe N-containing optionally substituted bicyclic heterocycloalkyl or anN-containing optionally substituted tricyclic heterocycloalkyl isoctahydropyrrolo[3,4-c]pyrrolyl, decahydro-2,6-naphthyridinyl,decahydro-2,7-naphthyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, or2,6-diazaspiro[3.3]heptanyl.

In some embodiments ring B is

In some embodiments, G is -L¹-R^(d); L¹ is absent; and R^(d) is anoptionally substituted C₃-C₆cycloalkyl.

In some embodiments R^(d) is

R¹ is hydrogen, halogen, C₁-C₄alkyl or C₁-C₄haloalkyl;

-   -   and m is 1 or 2.

In some embodiments, R¹ is hydrogen, halogen, C₁-C₄alkyl, orC₁-C₄haloalkyl. In some embodiments, R¹ is hydrogen, F, C₁-C₄alkyl, orC₁-C₄fluoroalkyl.

In some embodiments R¹ is F or C₁-C₄fluoroalkyl. In some embodiments R¹is F or CF₃.

In some embodiments R^(d) is cyclopropyl, cyclobutyl, or cyclopentyl. Insome embodiments, R^(d) is cyclopropyl. In some embodiments R¹ is F,methyl, or CF₃. In some embodiment R¹ is F.

In some embodiments R⁸ is C₁-C₄alkoxy, or —N(R^(a))₂; and R⁷ ishydrogen, halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, orC₁-C₄haloalkoxy. In some embodiment R⁸ is methoxy or —N(R^(a))₂. In someembodiments —N(R^(a))₂ is dimethylamino, azeridinyl, or azetidinyl. Insome embodiments —N(R^(a))₂ is azetidinyl. In some embodiments R⁷ ishydrogen or halogen. In some embodiments R⁷ is hydrogen.

Non-limiting examples of compounds of Formula (I), (II), (III), (IV),(V), (VI), (VII) or (VIII), include:

or pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof of any one of the preceding compounds.Further Forms of Compounds

In one aspect, the compound of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII), possesses one or more stereocenters and eachstereocenter exists independently in either the R or S configuration.The compounds presented herein include all diastereomeric, enantiomeric,and epimeric forms as well as the appropriate mixtures thereof. Thecompounds and methods provided herein include all cis, trans, syn, anti,entgegen (E), and zusammen (Z) isomers as well as the appropriatemixtures thereof. In certain embodiments, compounds described herein areprepared as their individual stereoisomers by reacting a racemic mixtureof the compound with an optically active resolving agent to form a pairof diastereoisomeric compounds/salts, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,resolution of enantiomers is carried out using covalent diastereomericderivatives of the compounds described herein. In another embodiment,diastereomers are separated by separation/resolution techniques basedupon differences in solubility. In other embodiments, separation ofsteroisomers is performed by chromatography or by the formingdiastereomeric salts and separation by recrystallization, orchromatography, or any combination thereof. Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981. In one aspect, stereoisomers are obtained bystereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) to facilitatetransmittal across a cell membrane where water solubility is detrimentalto mobility but which then is metabolically hydrolyzed to the carboxylicacid, the active entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

In one aspect, prodrugs are designed to alter the metabolic stability orthe transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacokinetic, pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is known, the design prodrugs ofthe compound is possible. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho,“Recent Advances in Oral Prodrug Discovery”, Annual Reports in MedicinalChemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series).

In some cases, some of the herein-described compounds may be a prodrugfor another derivative or active compound.

In some embodiments, sites on the aromatic ring portion of compoundsdescribed herein are susceptible to various metabolic reactionsTherefore incorporation of appropriate substituents on the aromatic ringstructures will reduce, minimize or eliminate this metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a halogen, or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, suchas, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl. In oneaspect, isotopically-labeled compounds described herein, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. In one aspect, substitution with isotopes such as deuteriumaffords certain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

“Pharmaceutically acceptable” as used herein, refers a material, such asa carrier or diluent, which does not abrogate the biological activity orproperties of the compound, and is relatively nontoxic, i.e., thematerial may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, pharmaceuticallyacceptable salts are obtained by reacting a compound of Formula (I),(II), (III), (IV), (V), (VI), (VII) or (VIII) with acids.Pharmaceutically acceptable salts are also obtained by reacting acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII)with a base to form a salt.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms, particularlysolvates. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and may be formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates ofcompounds described herein can be conveniently prepared or formed duringthe processes described herein. In addition, the compounds providedherein can exist in unsolvated as well as solvated forms. In general,the solvated forms are considered equivalent to the unsolvated forms forthe purposes of the compounds and methods provided herein.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FisherScientific (Fisher Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compounds as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein. As a guidethe following synthetic methods may be utilized.

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. A detailed description oftechniques applicable to the creation of protecting groups and theirremoval are described in Greene and Wuts, Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, andKocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, whichare incorporated herein by reference for such disclosure).

In some embodiments, compounds described herein are prepared as shown inScheme A.

In some embodiments, the synthesis of quinazoline-derived compounds 1-6described herein is accomplished starting from suitably substitutedmethyl anthranilates 1-1 as shown in Scheme A. Acid catalyzed (i.e. HCl)condensation of substituted methyl anthranilates (1-1) with substitutedcarbonitrile affords 4-hydroxyquinazoline intermediates (1-4).Chlorination (i.e. POCl₃) of the 4-hydroxyquinazoline intermediatesfollowed by amination of the resulting 4-chloroquinazoline intermediates(1-5) with various substituted aryl piperidines, piperazines orpyrrolidines affords quinazoline analogs 1-6. In some embodiments, the4-hydroxyquinazoline intermediates (1-4) are directly reacted withvarious substituted aryl piperidines, piperazines or pyrrolidines usinga coupling reagent (i.e. BOP) and a base (i.e. DBU) to affordquinazoline analogs 1-6. In some embodiments, the synthesis of the4-hydroxyquinazoline intermediates (1-4) is accomplished in two stepsby 1) amide condensation of a substituted anthranilonitrile (1-3) and asubstituted carboxylic acid using an amide coupling reagent (i.e HATU)to afford N-(2-cyanophenyl)amide derivatives 1-2 and 2) cyclizationunder basic (i.e. NaOH) and oxidative (i.e. H₂O₂) conditions to afford4-hydroxyquinazoline intermediates (1-4).

In some embodiments, compounds described herein are prepared as shown inScheme B.

In some embodiments, suitably substituted anthranilic acids 2-1 are usedto prepare quinazoline compounds 2-5 as shown in Scheme B. In someembodiments, cyclization of anthranilic acid 2-1 with a cyanate salt(i.e. KOCN) affords quinazoline-(1H,3H)-dione compound 2-2. In someembodiments, quinazoline-(1H,3H)-dione compound 2-2 is chlorinated toyield 2,4-dichloroquinazoline compound 2-3. In some embodiments, thechlorinating agent is POCl₃. In some embodiments, dichloroquinazolinecompound 2-3 are selectively aminated at the 4-position using anoptionally substituted aryl piperidine, aryl piperazines or arylpyrrolidines to yield compounds of structure 2-4. In some embodiments, apalladium calalyzed Suzuki type reaction with compounds of structure 2-4and a suitably substituted boronic acid afforded the quinazoline analogs2-5.

In some embodiments, compounds described herein are prepared as shown inScheme C.

In some embodiment, suitably substituted bromo-quinazolin-4-ol 3-la(synthesized from procedures described in either Scheme A or Scheme B)were reacted with a suitably substituted aniline 3-2 using Buchwald typereaction conditions to afford quinazoline derivatives 3-3. In somealternative embodiments, a suitably substituted nitro-quinazolin-4-ol3-1b (synthesized from procedures described in either Scheme A or SchemeB) were hydrogenated to the aniline derivatives 3-4. In some embodimentthese anilines were further reacted with an alkyl halide (3-5) to affordquinazoline derivatives 3-3. In some embodiments, the quinazolinederivatives 3-3 are further functionalized by reacting a suitablysubstituted aldehyde using reductive amidation conditions to providederivatives 3-6. In some embodiments, when X is O and R¹⁰ is a silylprotecting group, quinazoline derivatives 3-6 can be deprotected in thepresence of a fluoride source to provide compounds 3-7.

In some embodiments, compounds described herein are prepared as shown inScheme D.

In some embodiment, the 2-chloro on the nitro substituted quinazolinering of compounds 4-1 is displaced by a suitable amine to providecompounds 4-2. In some embodiment the nitro group is reduced to an aminoto yield compounds 4-3. In some embodiments, quinazoline 4-3 can befurther reacted with an appropriate alkyl halide (4-4) to providesubstituted quinazolines 4-5 which can be, in some embodiments furtherfunctionalized using an appropriate aldehyde under reductive aminationconditions to provide compounds 4-6.

It will be understood that the reactions shown above are illustrative.

In one aspect, compounds are synthesized as described in the Examplessection.

Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contentclearly dictates otherwise. It should also be noted that the term “or”is generally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radical,having from one to thirty carbon atoms, and which is attached to therest of the molecule by a single bond. Alkyls comprising any number ofcarbon atoms from 1 to 10 are included. An alkyl comprising up to 10carbon atoms is referred to as a C₁-C₁₀ alkyl, likewise, for example, analkyl comprising up to 6 carbon atoms is a C₁-C₆ alkyl. Alkyls (andother moieties defined herein) comprising other numbers of carbon atomsare represented similarily. Alkyl groups include, but are not limitedto, C₁-C₁₀ alkyl, C₁-C₉ alkyl, C₁-C₈ alkyl, C₁-C₇ alkyl, C₁-C₆ alkyl,C₁-C₅ alkyl, C₁-C₄ alkyl, C₁-C₃ alkyl, C₁-C₂ alkyl, C₂-C₈ alkyl, C₃-C₈alkyl and C₄-C₈ alkyl. Representative alkyl groups include, but are notlimited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwisespecifically in the specification, an alkyl group may be optionallysubstituted as described below. “Alkylene” or “alkylene chain” refers toa straight or branched divalent hydrocarbon chain linking the rest ofthe molecule to a radical group.

“Alkoxy” refers to a radical of the formula —OR where R is an alkylradical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed below.

“Heteroalkylene” refers to an alkyl radical as described above where oneor more carbon atoms of the alkyl is replaced with a O, N or S atom.“Heteroalkylene” or “heteroalkylene chain” refers to a straight orbranched divalent heteroalkyl chain linking the rest of the molecule toa radical group. Unless stated otherwise specifically in thespecification, the heteroalkyl or heteroalkylene group may be optionallysubstituted as described below. Representative heteroalkyl groupsinclude, but are not limited to —OCH₂CH₂OMe, OCH₂CH₂OCH₂CH₂NH₂, orOCH₂CH₂OCH₂CH₂OCH₂CH₂N(Me)₂.

Representative heteroalkylene groups include, but are not limited to—OCH₂CH₂O—, OCH₂CH₂OCH₂CH₂O—, or OCH₂CH₂OCH₂CH₂OCH₂CH₂O—.

“Alkylamino” refers to a radical of the formula —NHR or —NRR where eachR is, independently, an alkyl radical as defined above. Unless statedotherwise specifically in the specification, an alkylamino group may beoptionally substituted as described below.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl radicals include, but are not limited to, aryl radicalsderived from the hydrocarbon ring systems of benzene, indane, indene,and naphthalene. Unless stated otherwise specifically in thespecification, the term “aryl” or the prefix “ar-” (such as in“aralkyl”) is meant to include aryl radicals that are optionallysubstituted.

“Carboxy” refers to CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

“Cycloalkyl” refers to a stable, non-aromatic, monocyclic or polycycliccarbocyclic ring, which may include fused or bridged ring systems, whichis saturated or unsaturated, and attached to the rest of the molecule bya single bond. Representative cycloalkyls include, but are not limitedto, cycloaklyls having from three to fifteen carbon atoms, from three toten carbon atoms, from three to eight carbon atoms, from three to sixcarbon atoms, from three to five carbon atoms, or three to four carbonatoms. Monocyclic cyclcoalkyl radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unlessotherwise stated specifically in the specification, a cycloalkyl groupmay be optionally substituted. Illustrative examples of cycloalkylgroups include, but are not limited to, the following moieties:

and the like.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure. When the fused ring is a heterocyclyl ringor a heteroaryl ring, any carbon atom on the existing ring structurewhich becomes part of the fused heterocyclyl ring or the fusedheteroaryl ring may be replaced with a nitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

“Perhalo” or “perfluoro” refers to a moiety in which each hydrogen atomhas been replaced by a halo atom or fluorine atom, respectively.

“Heterocyclyl” or “heterocyclic ring” or “hetercycloalkyl” refers to astable 3- to 14-membered non-aromatic ring radical comprising 2 to 13carbon atoms and from one to 6 heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur. Unless stated otherwisespecifically in the specification, the heterocyclyl radical may be amonocyclic, or bicyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized; the nitrogen atom maybe optionally quaternized; and the heterocyclyl radical may be partiallyor fully saturated. Examples of such heterocyclyl radicals include, butare not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. Unless statedotherwise specifically in the specification, a heterocyclyl group may beoptionally substituted. Illustrative examples of heterocycloalkylgroups, also referred to as non-aromatic heterocycles, include:

and the like. The term heterocycloalkyl also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. In someembodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. Insome embodiments, heterocycloalkyls have from 2 to 8 carbons in the ringand 1 or 2 N atoms. It is understood that when referring to the numberof carbon atoms in a heterocycloalkyl, the number of carbon atoms in theheterocycloalkyl is not the same as the total number of atoms (includingthe heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atomsof the heterocycloalkyl ring). Unless stated otherwise specifically inthe specification, a heterocycloalkyl group may be optionallysubstituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. For purposes ofthis invention, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

All the above groups may be either substituted or unsubstituted. Theterm “substituted” as used herein means any of the above groups may befurther functionalized wherein at least one hydrogen atom is replaced bya bond to a non-hydrogen atom substituent. Unless stated specifically inthe specification, a substituted group may include one or moresubstituents selected from: oxo, —CO₂H, nitrile, nitro, hydroxyl,thiooxy, alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl,alkyloxycarbonyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl,aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl,cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl,cycloalkyloxycarbonyl, heterocyclyl, heteroaryl, dialkylamines,arylamines, alkylarylamines, diarylamines, perfluoroalkyl orperfluoroalkoxy, for example, trifluoromethyl or trifluoromethoxy.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. For example, “substituted” includes any of theabove groups in which one or more hydrogen atoms are replaced

with —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h),—OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g),—SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h). “Substituted” also meansany of the above groups in which one or more hydrogen atoms are replacedwith —C(═O)R_(g), —C(═O)OR_(g), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h), —SH,—SR_(g) or —SSR_(g). In the foregoing, R_(g) and R_(h) are the same ordifferent and independently hydrogen, alkyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. Inaddition, each of the foregoing substituents may also be optionallysubstituted with one or more of the above substituents. In someembodiments, optional substituents are independently selected fromhydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³, —C(═C)—N(R¹²)—R¹³,—NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —C—O(═O)—R¹¹, —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹,—N(R¹²)S(═O)₂R¹¹, —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted alkoxy, optionally substitutedhaloalkyl, optionally substituted haloalkoxy, optionally substitutedphenyl, and optionally substituted 5- or 6-membered heteroaryl; each ofR¹² and R¹³ is independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted alkoxy, optionally substituted haloalkyl, optionallysubstituted haloalkoxy, optionally substituted phenyl, and optionallysubstituted 5- or 6-membered heteroaryl; or R¹² and R¹³, when on thesame nitrogen atom, are taken together with the nitrogen atom to whichthey are attached to form an optionally substituted heterocycloalkyl;R¹⁵ is selected from the group consisting of optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted alkoxy, optionally substitutedhaloalkyl, optionally substituted haloalkoxy, optionally substitutedphenyl, and optionally substituted 5- or 6-membered heteroaryl. In someembodiments, optional substituents are independently selected fromhydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³, —C(═C)—N(R¹²)—R¹³,—NR¹²C(═O)R¹¹, —C(═O)—O—R¹¹, —C—O(═O)—R¹¹, —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹,—N(R¹²)S(═O)₂R¹¹, —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, alkyl, cycloalkyl,heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or6-membered heteroaryl; each of R¹² and R¹³ is independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or6-membered heteroaryl; or R¹² and R¹³, when on the same nitrogen atom,are taken together with the nitrogen atom to which they are attached toform an optionally substituted heterocycloalkyl; R¹⁵ is selected fromthe group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkoxy,haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) and a co-agent, are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the active ingredients, e.g. acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII)and a co-agent, are administered to a patient as separate entitieseither simultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, humans. In one embodiment, the mammalis a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseasedisease or condition, preventing additional symptoms, inhibiting thedisease or condition, e.g., arresting the development of the disease orcondition, relieving the disease or condition, causing regression of thedisease or condition, relieving a condition caused by the disease orcondition, or stopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

Administration and Pharmaceutical Composition

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII)with other chemical components (i.e. pharmaceutically acceptableinactive ingredients), such as carriers, excipients, binders, fillingagents, suspending agents, flavoring agents, sweetening agents,disintegrating agents, dispersing agents, surfactants, lubricants,colorants, diluents, solubilizers, moistening agents, plasticizers,stabilizers, penetration enhancers, wetting agents, anti-foaming agents,antioxidants, preservatives, or one or more combination thereof. Thepharmaceutical composition facilitates administration of the compound toan organism.

Pharmaceutical formulations described herein are administerable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular, intramedullary injections, intrathecal,direct intraventricular, intraperitoneal, intralymphatic, intranasalinjections), intranasal, buccal, topical or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

In some embodiments, the compounds of Formula (I), (II), (III), (IV),(V), (VI), (VII) or (VIII) are administered orally.

In some embodiments, the compounds of Formula (I), (II), (III), (IV),(V), (VI), (VII) or (VIII) are administered topically. In suchembodiments, the compound of Formula (I), (II), (III), (IV), (V), (VI),(VII) or (VIII) is formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages,balms, creams or ointments. In one aspect, the compounds of Formula (I),(II), (III), (IV), (V), (VI), (VII) or (VIII) are administered topicallyto the skin.

In another aspect, the compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered by inhalation.

In another aspect, the compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are formulated for intranasal administration. Suchformulations include nasal sprays, nasal mists, and the like.

In another aspect, the compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are formulated as eye drops.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), (II), (III), (IV),(V), (VI), (VII) or (VIII) is: (a) systemically administered to themammal; and/or (b) administered orally to the mammal; and/or (c)intravenously administered to the mammal; and/or (d) administered byinhalation to the mammal; and/or (e) administered by nasaladministration to the mammal; or and/or (f) administered by injection tothe mammal; and/or (g) administered topically to the mammal; and/or (h)administered by ophthalmic administration; and/or (i) administeredrectally to the mammal; and/or (j) adminstered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner.

In some embodiments, the compound described herein is administeredtopically. In some embodiments, the compound described herein isadministered systemically.

In some embodiments, the pharmaceutical formulation is in the form of atablet. In other embodiments, pharmaceutical formulations of thecompounds of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII)are in the form of a capsule.

In one aspect, liquid formulation dosage forms for oral administrationare in the form of aqueous suspensions or solutions selected from thegroup including, but not limited to, aqueous oral dispersions,emulsions, solutions, elixirs, gels, and syrups.

For administration by inhalation, a compound of Formula (I), (II),(III), (IV), (V), (VI), (VII) or (VIII) is formulated for use as anaerosol, a mist or a powder.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, or gels formulated in a conventional manner.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are prepared as transdermal dosage forms.

In one aspect, a compound of Formula (I), (II), (III), (IV), (V), (VI),(VII) or (VIII) is formulated into a pharmaceutical composition suitablefor intramuscular, subcutaneous, or intravenous injection.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments.

In some embodiments, the compounds of Formula (I), (II), (III), (IV),(V), (VI), (VII) or (VIII) are formulated in rectal compositions such asenemas, rectal gels, rectal foams, rectal aerosols, suppositories, jellysuppositories, or retention enemas.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are used in the preparation of medicaments for thetreatment of diseases or conditions described herein. In addition, amethod for treating any of the diseases or conditions described hereinin a subject in need of such treatment, involves administration ofpharmaceutical compositions that include at least one compound ofFormula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) or apharmaceutically acceptable salt, active metabolite, prodrug, or solvatethereof, in therapeutically effective amounts to said subject.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition.

In certain embodiments, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”).

Doses employed for adult human treatment are typically in the range of0.01 mg-5000 mg per day or from about 1 mg to about 1000 mg per day. Inone embodiment, the desired dose is conveniently presented in a singledose or in divided doses.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII)in combination with another therapeutic agent.

In one specific embodiment, a compound of Formula (I), (II), (III),(IV), (V), (VI), (VII) or (VIII) is co-administered with a secondtherapeutic agent, wherein the compound of Formula (I), (II), (III),(IV), (V), (VI), (VII) or (VIII) and the second therapeutic agentmodulate different aspects of the disease, disorder or condition beingtreated, thereby providing a greater overall benefit than administrationof either therapeutic agent alone.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drug(s)employed, on the specific drug(s) employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

If administration is simultaneous, the multiple therapeutic agents are,by way of example only, provided in a single, unified form, or inmultiple forms.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered to a mammal in combination withan anti-inflammatory agent. In some embodiments, compounds of Formula(I), (II), (III), (IV), (V), (VI), (VII) or (VIII) are administered incombination with an anti-psychotic agent. In some embodiments, compoundsof Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) areadministered to a mammal in combination with a neuroleptic. In someembodiments, compounds of Formula (I), (II), (III), (IV), (V), (VI),(VII) or (VIII) are administered to a mammal in combination with anatypical antipsychotic. In some embodiments, compounds of Formula (I),(II), (III), (IV), (V), (VI), (VII) or (VIII) are administered incombination with a dopamine agonist. In some embodiments, compounds ofFormula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) areadministered in combination with an anticholinergic. In someembodiments, compounds of Formula (I), (II), (III), (IV), (V), (VI),(VII) or (VIII) are administered in combination with a COMT inhibitor.In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered to a mammal in combination withan analgesic. In some embodiments, compounds of Formula (I), (II),(III), (IV), (V), (VI), (VII) or (VIII) are administered to a mammal incombination with an antidepressant.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered to a mammal in combination withan NSAID, COX-2 inhibitor, opiate, morphinomimetic, or combinationsthereof.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered in combination with ananti-schizophrenia drug. In some embodiments, compounds of Formula (I),(II), (III), (IV), (V), (VI), (VII) or (VIII) are administered to amammal in combination with thorazine, haloperidol, fluphenazine,tiotixene, trifluoperazine, perphenazine, thioridazine, clozapine,aripiprazole, ziprasidone, paliperidone, lurasidone, risperidone,asenapine, quetiapine, olanzapine, dihydrexidine, roxindole orcombinations thereof.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered in combination with ananti-Parkinson's drug. In some embodiments, compounds of Formula (I),(II), (III), (IV), (V), (VI), (VII) or (VIII) are administered incombination with L-DOPA, carbidopa, carbidopa/L-DOPA, ropinirole,pramipexole, rotigotine, amantadine, trihexyphenidyl, benzatropine,selegiline, rasagiline, tolcapone, entacapone, apomorphine,bromocriptine, dihydrexidine, dinapsoline, lisuride, pergolide,piribedil, roxindole, sumanirole, or combinations thereof.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered to a mammal in combination withother therapeutics used in the treatment of drug abuse.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered to a mammal in combination with astroke treatment. In some embodiments, compounds of Formula (I), (II),(III), (IV), (V), (VI), (VII) or (VIII) are administered to a mammal incombination with a thrombolytic. In some embodiments, compounds ofFormula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) areadministered to a mammal in combination with tissue plasminogenactivator (tPA), or a recombinant tissue plasminogen activator. In someembodiments, compounds of Formula (I), (II), (III), (IV), (V), (VI),(VII) or (VIII) are administered to a mammal in combination withalteplase, reteplase, tenecteplase, or combinations thereof.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),(VI), (VII) or (VIII) are administered to a mammal in combination with atreatment for neuropathic pain. In some embodiments, compounds ofFormula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) areadministered to a mammal in combination with duloxetine, venlafaxine,and milnacipran, amitriptyline, nortriptyline, desipramine, bupropion,pregabalin, gabapentin, carbamazepine, oxcarbazepine, lamotrigine,methadone, ketobemidone, lidocaine, gallium maltolate, capsaicin,botulinum toxin type A, ketamine, dextromethorphan, memantine, alphalipoic acid, benfotiamine, and combinations thereof.

EXAMPLES

The following examples are intended to illustrate but not limit thedisclosed embodiments. All reactions involving air andmoisture-sensitive reagents and solvents were performed under a nitrogenatmosphere using standard chemical techniques. Anhydrous solvents werepurchased and freshly used from Sigma-Aldrich or EMD Biosciences. Allorganic reagents were used as purchased. Analytical thin-layerchromatography was performed on Partisil K6F silica gel 60 Å, 250 μm.Microwave-assisted reactions were performed using a CEM Discover system.¹H and ¹³C chemical shifts are reported in 6 values in ppm in thecorresponding solvent. All solvents used for chromatography on thesynthetic materials were Fisher Scientific HPLC grade, and the water wasMillipore Milli-Q PP filtered. LCMS analysis of synthetic materials wascompleted on a Waters Autopurification system, which consists of a 2767sample manager, a 2545 binary gradient module, a system fluidicsorganizer, a 2489 UV/vis detector, and a 3100 mass detector, allcontrolled with MassLynx software. A Sunfire Analytical C18 5 nm column(4.6×50 mm) and stepwise gradient {10% [(MeCN+0.1% TFA) in (water+0.1%TFA)] to 98% [(MeCN+0.1% TFA) in (water+0.1% TFA)] for 9 min.} was usedfor analytical LCMS of final compounds. The final compounds werepurified by silica gel flash chromatography with ethyl acetate/hexanesas the eluant. All NMR spectra for the synthetic materials were recordedon a Bruker Avance II 400 or DRX-500 MHz instrument. The MestReNova 7program was used to process and interpret NMR spectra. High ResolutionMass Spectrometry (HRMS) spectra were carried out on an Agilent 6224AAccurate-Mass Time-of-Flight (TOF) LC/MS system with electron sprayionization (ESI).

Example 1: Preparation of{4-[4-(2-azetidin-1-yl-phenyl)-piperazin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-dimethyl-amine

A mixture of 1,2-dibromobenzene (2.36 g, 10 mmol),piperazine-1-carboxylic acid tert-butyl ester (1.86 g, 10 mmol),Pd(OAc)₂ (224.5 mg, 1.0 mmol), BINAP (1.2 g, 2.0 mmol), Cs₂CO₃ (6.5 g,20 mmol) and toluene/1,4-dioxaen (15 mL/15 mL) was heated to 90° C.overnight. The reaction mixture was filtered and the filtrate wasconcentrated to dryness. The residue was purified by silica gel columnchromatography (PE/EtOAc=1/50) to afford tert-butyl4-(2-bromophenyl)piperazine-1-carboxylate (1.8 g, yield: 53%) as acolorless oil.

A mixture of tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate (1.5g, 4.4 mmol) and HCl/EtOAc (2M, 20 mL) was stirred for 1 hour at roomtemperature. The reaction mixture was filtered and the solid was driedto afford 1-(2-bromophenyl)piperazine (1.0 g, yield: 85%) as a whitesolid. A mixture of 2-cyclopropyl-6-nitro-quinazolin-4-ol (700 mg, 3.0mmol), 1-(2-bromophenyl)piperazine (924 mg, 3.33 mmol), BOP (2.0 g, 4.54mmol) and DBU (921 mg, 6.06 mmol) in MeCN (20 mL) was stirred at roomtemperature overnight. The reaction mixture was filtered and thefiltrate was concentrated to dryness in vacuum. The residue was purifiedby silica gel column chromatography (PE/EtOAc=1/50) to afford4-(4-(2-bromophenyl)piperazin-1-yl)-2-cyclopropyl-6-nitroquinazoline(550 mg, yield: 40%) as a yellow semi-solid.

A mixture of4-(4-(2-bromophenyl)piperazin-1-yl)-2-cyclopropyl-6-nitroquinazoline(550 mg, 1.21 mmol), active iron powder (340 mg, 6.05 mmol), saturatedaqueous NH₄Cl solution (10 mL) in MeOH (20 mL) was heated to 85° C. for2 hours. After cooled to room temperature, the mixture was filteredthrough celite. The filtrate was concentrated to remove most of theorganic solvent. The aqueous phase was extracted with DCM (10 mL×2). Thecombined organic layers were dried over Na₂SO₄ and concentrated to givecrude product. The crude product was purified by silica gel columnchromatography (MeOH/DCM=1/20) to afford4-(4-(2-bromophenyl)piperazin-1-yl)-2-cyclopropylquinazolin-6-amine (350mg, yield: 68%) as a yellow semi-solid.

A solution of4-(4-(2-bromophenyl)piperazin-1-yl)-2-cyclopropylquinazolin-6-amine (300mg, 0.71 mmol), NaBH₃CN (447.3 mg, 7.1 mmol), HCHO (40% in H₂O, 0.5 mL)in MeOH (5 mL) was stirred at room temperature overnight. 15 mL of waterwas added and the mixture was extracted with EtOAc (15 mL×3). Theorganic layer was washed with water (15 mL) and brine (15 mL) and driedover Na₂SO₄. The solution was concentrated to give a residue, which waspurified by prep-TLC to afford4-(4-(2-bromophenyl)piperazin-1-yl)-2-cyclopropyl-N,N-dimethylquinazolin-6-amine(250 mg, yield: 78%) as a yellow semi-solid.

A mixture of4-(4-(2-bromophenyl)piperazin-1-yl)-2-cyclopropyl-N,N-dimethylquinazolin-6-amine(150 mg, 0.33 mmol), azetidine (38 mg, 0.66 mmol), Pd(OAc)₂ (7.4 mg,0.033 mmol), BINAP (41 mg, 0.066 mmol), Cs₂CO₃ (324 mg, 0.99 mmol) andtoluene/1,4-dioxane (5 mL/5 mL) was heated to 90° C. overnight. Thereaction mixture was filtered and the filtrate was concentrated todryness. The residue was purified by silica gel column chromatography(PE/EtOAc=3/7) then by prep-HPLC to afford{4-[4-(2-azetidin-1-yl-phenyl)-piperazin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-dimethyl-amine(33 mg, yield: 21%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.59(d, J=12.4 Hz, 1H), 7.46-7.43 (m, 1H), 7.02-6.91 (m, 2H), 6.81-6.73 (m,2H), 6.48-6.46 (m, 1H), 3.89-3.84 (m, 4H), 3.74-3.67 (m, 4H), 3.07-3.00(m, 10H), 2.21-2.07 (m, 3H), 1.02-0.99 (m, 2H), 0.94-0.89 (m, 2H). MS:m/z 429.3 (M+H⁺).

Example 2: Preparation of{4-[4-(2-azetidin-1-yl-phenyl)-piperazin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-ethyl-methyl-amine

The title compound was prepared as described for{4-[4-(2-azetidin-1-yl-phenyl)-piperazin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-dimethyl-amineexcept that formaldehyde was substituted for acetaldehyde. ¹H NMR (400MHz, CDCl₃): δ=7.74 (d, J=7.6 Hz, 1H), 7.32 (d, J=10.4 Hz, 1H),7.05-7.00 (m, 2H), 6.83-6.79 (m, 2H), 6.53 (d, J=8.4 Hz, 1H), 3.97-3.93(m, 4H), 3.78-3.70 (m, 4H), 3.50-3.44 (m, 2H), 3.15 (m, 4H), 2.98 (s,3H), 2.26-2.19 (m, 3H), 1.17-1.14 (m, 5H), 0.98-0.96 (m, 2H). MS: m/z443.3 (M+H⁺).

Example 3: Preparation of4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-dimethyl-amine

LDA (2M, 65 mL) was added to a solution of 4-oxo-piperidine-1-carboxylicacid tert-butyl ester (20 g, 100 mmol) in 300 mL of dry THF at −78° C.and the mixture was stirred for 30 min. A solution ofN,N-bis-(trifluoromethanesulfonyl)aniline in dry THF (100 mL) was addedslowly at −78° C. and the mixture was allowed to warm to roomtemperature and stirred overnight. The reaction was quenched with sat.NH₄Cl solution (50 mL) and water (400 mL). The mixture was extractedwith EtOAc (200 mL). The organic layer was washed with water (50 mL) andbrine (50 mL), and dried over Na₂SO₄. The solution was concentrated todryness and the residue was purified by silica gel column chromatography(PE/EA=50/1) to give compound4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (24.5 g, yield: 74%) as a yellow oil. ¹H NMR (300 MHz,CDCl₃): δ=5.76 (s, 1H), 4.04 (d, J=1.8 Hz, 2H), 3.62 (t, J=5.6 Hz, 2H),2.43 (s, 2H), 1.47 (s, 9H).

A mixture of compound4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (24.5 g, 74 mmol), bis(pinacolato)diboron (21.6 g, 85mmol), KOAc (25.4 g, 259 mmol), Pd(dppf)Cl₂ (1.6 g, 2.22 mmol), dppf(1.23 g, 2.22 mmol) and 250 mL of 1,4-dioxane was stirred at 80° C.overnight. The reaction mixture was poured into water (500 mL) andextracted with EtOAc (200 mL). The organic layer was washed with water(100 mL) and brine (100 mL), dried over Na₂SO₄, concentrated andpurified by silica gel column (PE/EA=20/1) to give compound4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (28 g, quantitative) as a white solid. ¹H NMR (300MHz, CDCl₃): δ=6.45 (s, 1H), 3.94 (d, J=2.7 Hz, 2H), 3.62 (t, J=5.6 Hz,2H), 2.22 (s, 2H), 1.45 (s, 9H), 1.25 (s, 12H).

A mixture of compound4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (16.1 g, 52 mmol), 1-bromo-2-iodo-benzene (9.8 g,35 mmol), K₂CO₃ (19.3 g, 140 mmol), Pd(dppf)Cl₂ (1.25 g, 1.75 mmol), 225mL of 1,4-dioxane and 75 mL of water was stirred at 70° C. overnight.The reaction mixture was poured into water (500 mL) and extracted withEtOAc (300 mL). The organic layer was washed with water and brine, driedover Na₂SO₄, concentrated and purified by silica gel column (PE/EA=60/1)to give compound 4-(2-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (8 g, yield: 67%) as a white solid. ¹H NMR (300MHz, CDCl₃): δ=7.55 (d, J=7.8 Hz, 1H), 7.29-7.24 (m, 1H), 7.1-7.09 (m,2H), 5.62 (s, 1H), 4.04 (d, J=2.1 Hz, 2H), 3.64 (t, J=5.6 Hz, 2H), 2.42(s, 2H), 1.50 (s, 9H).

A mixture of compound4-(2-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester (7.1 g, 20.11 mmol), azetidine (1.4 g, 24.1 mmol), Pd(AcO)₂ (451mg, 2.01 mmol), BINAP (2.5 g, 4.02 mmol), Cs₂CO₃ (13.07 g, 40.22 mmol)and toluene/1,4-dioxane (40 mL/40 mL) was stirred at 90° C. Filtrationand concentration resulted in a brown residue which was purified bysilica gel column (PE/EA=60/1) to give compound4-(2-azetidin-1-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (5.0 g, 79%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃):δ=7.16-7.12 (m, 1H), 6.96 (dd, J=7.8, 7.5 Hz, 1H), 6.76 (t, J=7.4 Hz,1H), 6.48 (d, J=8.1 Hz, 1H), 5.62 (m, 1H), 4.01 (d, J=2.1 Hz, 2H), 3.78(t, J=7.2 Hz, 4H), 3.61 (t, J=5.6 Hz, 2H), 2.40 (s, 2H), 2.26-2.16 (m,2H), 1.49 (s, 9H).

A mixture of to give compound4-(2-azetidin-1-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (5.0 g, 15.9 mmol), wet 10% Pd/C (1 g) and MeOH (200mL) was stirred at 40° C. under 50 psi of H₂ overnight. The reactionmixture was filtered and concentrated to give compound4-(2-azetidin-1-yl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester(5.0 g, quantitive) as a colorless oil.

A mixture of compound 4-(2-azetidin-1-yl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (5.0 g, 15.9 mmol) was dissolved in DCM (80 mL),CF₃CO₂H (80 mL) was added and stirred at room temperature for 2 hours.The reaction solution was concentrated and the residue was treated withsaturated NaHCO₃ solution (100 mL) and extracted with EtOAc (100 mL×5).The organic layer was combined and washed with brine, dried over Na₂SO₄and concentrated to give compound 4-(2-azetidin-1-yl-phenyl)-piperidine(2.5 g, yield: 74%) as a white solid.

The title compound was prepared as described for{4-[4-(2-azetidin-1-yl-phenyl)-piperazin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-dimethyl-aminefor the last 3 steps. ¹HNMR (300 MHz, CDCl₃): δ=7.78-7.76 (m, 1H), 7.35(dd, J=9.3 Hz, 1H), 7.24-7.15 (m, 2H), 6.93-6.87 (m, 2H), 6.64-6.61 (m,1H), 4.41-4.37 (m, 2H), 3.96 (t, J=7.1 Hz, 4H), 3.81-3.04 (m, 8H),2.35-2.23 (m, 3H), 2.04-1.91 (m, 5H), 1.18-1.15 (m, 2H), 1.00-0.97 (m,2H). MS: m/z 428.2 (M+H⁺).

Example 4: Preparation of{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-ethyl-methyl-amine

To a solution of 6-bromo-2-cyclopropylquinazolin-4-ol (530 mg, 2.0 mmol)in ACN (50 mL) were added 4-(2-(azetidin-1-yl)phenyl)piperidine (475 mg,2.2 mmol), BOP (1.33 g, 3 mmol) and DBU (912 mg, 6.0 mmol). The mixturewas stirred at room temperature overnight. The resulting solid wascollected by filtration to give the desired compound. The filtrate waspoured into water (50 mL) and extracted with EtOAc (20 mL). The organiclayer was washed with water and brine and dried over anhydrous Na₂SO₄.The solvent was removed and the residue was purified by silica gelcolumn chromatography (PE/EA, 10/1-5/1) to give4-(4-(2-(azetidin-1-yl)phenyl)piperidin-1-yl)-6-bromo-2-cyclopropylquinazoline(590 mg, yield: 64%) as a white solid. ¹HNMR (300 MHz, CDCl₃): δ=7.96(d, J=2.1 Hz, 1H), 7.74-7.64 (m, 2H), 7.20-7.13 (m, 2H), 6.89 (t, J=7.5Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 4.39 (d, J=12.9 Hz, 2H), 3.96 (t,J=7.2, 4H), 3.32-3.02 (m, 3H), 2.34-2.29 (m, 2H), 2.21-2.15 (m, 1H),2.03-1.86 (m, 4H), 1.20-1.15 (m, 2H), 1.03-0.97 (m, 2H). MS: m/z 462.9(M+H⁺).

A mixture of4-(4-(2-(azetidin-1-yl)phenyl)piperidin-1-yl)-6-bromo-2-cyclopropylquinazoline(100 mg, 0.22 mmol), N-methylethanamine (26 mg, 0.44 mmol), Pd(OAc)₂ (5mg, 0.022 mmol), BINAP (27.4 mg, 0.044 mmol), Cs₂CO₃ (143 mg, 0.44 mmol)and toluene/1,4-dioxaen (5 mL/5 mL) was heated to 90° C. overnight. Thereaction mixture was filtered and the filtrate was concentrated todryness. The residue was purified by prep-TLC (pure EtOAc) then byprep-HPLC to afford{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-ethyl-methyl-amine(24 mg, yield: 21%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃):δ=7.77-7.74 (m, 1H), 7.33-7.13 (m, 3H), 6.92-6.83 (m, 2H), 6.10 (d,J=8.4 Hz, 1H), 4.40-4.36 (m, 2H), 3.94 (t, J=6.9 Hz, 4H), 3.51-3.45 (m,2H), 3.12-2.98 (m, 6H), 2.33-2.22 (m, 3H), 2.04-1.89 (m, 4H), 1.30-1.10(m, 5H), 0.98-0.96 (m, 2H). MS: m/z 442.3 (M+H⁺).

Example 5: Preparation ofN-{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-N,N′,N′-trimethyl-ethane-1,2-diamine

The title compound was prepared as described for{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-ethyl-methyl-amine.¹H NMR (400 MHz, DMSO-d₆): δ=7.57 (d, J=9.2 Hz, 1H), 7.39 (dd, J=9.2,2.8 Hz, 1H), 7.15 (d, J=6.8 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 6.80-6.77(m, 2H), 6.52 (d, J=8.0 Hz, 1H), 4.23 (d, J=12.4 Hz, 2H), 3.87 (t, J=6.8Hz, 4H), 3.51 (t, J=7.2 Hz, 2H), 3.09-2.94 (m, 6H), 2.41-2.38 (m, 2H),2.25-2.17 (m, 8H), 2.06-2.02 (m, 1H), 1.90-1.79 (m, 4H), 1.01- 0.97 (m,2H), 0.91-0.87 (m, 2H). MS: m/z 485.3 (M+H⁺).

Example 6: Preparation of2-({4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-amino)-ethanol

A mixture of4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-6-bromo-2-cyclopropyl-quinazoline(150 mg, 0.32 mmol), 2-(tert-Butyl-dimethyl-silanyloxy)-ethylamine (112mg, 0.64 mmol), Pd(OAc)₂ (7.2 mg, 0.032 mmol), BINAP (46 mg, 0.064mmol), Cs₂CO₃ (209 mg, 0.64 mmol) and toluene/1,4-dioxaen (5 mL/5 mL)was heated to 90° C. overnight. The reaction mixture was filtered andthe filtrate was concentrated to afford crude{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amine(crude 350 mg, yield: quantitative) as a yellow gel.

To the solution of crude{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amine(crude 350 mg, 0.32 mmol) in MeOH (20 mL) was added HCHO (38% in H₂O,0.52 mL), followed by NaBH(AcO)₃ (678 mg, 3.2 mmol) and NaBH₃CN (202 mg,3.2 mmol). The solution was stirred at RT overnight. The resultingsolution was poured into sat. NaHCO₃ solution (30 mL) and the aqueousphase was extracted with EtOAc (20 mL). The organic layer was washedwith water and brine, dried over Na₂SO₄, concentrated to give crude{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amine(used for next step directly without purification) as a yellow gel.

To the solution of crude{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amine(crude, 0.32 mmol) in THF (10 mL) was added TBAF (1 M in THF, 1 mL). Thesolution was stirred at RT overnight. The resulting solution wasconcentrated, purified by prep-TLC (DCM/MeOH=10/1) then further purifiedby prep-HPLC to give2-({4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-amino)-ethanol(30 mg, yield: 20% over 3 steps) as a yellow gel. ¹H NMR (300 MHz,CDCl₃): δ=7.70 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 2.7 Hz, 1H),7.24-7.14 (m, 2H), 6.96-6.90 (m, 2H), 6.62 (d, J=8.4, 1H), 4.37-4.31 (m,2H), 3.97-3.86 (m, 6H), 3.58-3.54 (m, 2H), 3.13-3.01 (m, 6H), 2.35-2.30(m, 2H), 2.20-2.18 (m, 1H), 2.00-1.89 (m, 4H), 1.17-1.14 (m, 2H),1.00-0.95 (m, 2H). MS: m/z 458.3 (M+H⁺).

Example 7: Preparation of{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-(2-methoxy-ethyl)-methyl-amine

The title compound was prepared as described for2-({4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.72 (d, J=9.2 Hz, 1H), 7.33 (d, J=8.4 Hz,1H), 7.22 (d, J=7.6 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 6.89-6.87 (m, 2H),6.61 (d, J=7.6 Hz, 1H), 4.34 (d, J=12.8 Hz, 2H), 3.94 (t, J=6.8 Hz, 4H),3.59 (s, 4H), 3.35 (s, 3H), 3.09-3.00 (m, 6H), 2.32-2.29 (m, 2H),2.20-2.18 (m, 1H), 1.98-1.90 (m, 4H), 1.17-1.14 (m, 2H), 0.96-0.94 (m,2H). MS: m/z 472.3 (M+H⁺).

Example 8: Preparation of{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({4-[4-(2-Azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.72 (d, J=9.6 Hz, 1H), 7.31 (dd, J=9.2, 2.8Hz, 1H), 7.21 (d, J=6.8 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 6.90-6.85 (m,2H), 6.61 (d, J=8.0 Hz, 1H), 4.33 (d, J=12.8 Hz, 2H), 3.94 (t, J=7.2 Hz,4H), 3.69 (t, J=4.4 Hz, 4H), 3.56 (t, J=7.2 Hz, 2H), 3.09-3.00 (m, 6H),2.58-2.50 (m, 6H), 2.34-2.27 (m, 2H), 2.20-2.16 (m, 1H), 2.02-1.90 (m,4H), 1.16-1.13 (m, 2H), 0.98-0.93 (m, 2H). MS: m/z 527.3 (M+H⁺).

Example 9: Preparation of{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

The title compound was prepared as described in2-({4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, DMSO-d₆): δ=7.57 (d, J=9.6 Hz, 1H), 7.38 (dd, J=9.2,2.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.07 (t, J=7.2 Hz, 1H), 6.80-6.76(m, 2H), 6.52 (d, J=8.0, 1H), 4.22 (d, J=12.4 Hz, 2H), 3.86 (t, J=7.6Hz, 4H), 3.53 (t, J=7.6 Hz, 2H), 3.08-2.92 (m, 6H), 2.61-2.50 (m, 6H),2.25-2.18 (m, 2H), 2.06-2.02 (m, 1H), 1.91-1.79 (m, 4H), 1.65 (s, 4H),1.01-0.98 (m, 2H), 0.91-0.87 (m, 2H). MS: m/z 511.3 (M+H⁺).

Example 10: Preparation of2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

A mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(10.1 g, 32.7 mmol), 1-bromo-2-nitro-benzene (4.4 g, 21.8 mmol), K₂CO₃(12.0 g, 87.2 mmol), Pd(dppf)Cl₂ (0.78 g, 1.09 mmol), 90 mL of1,4-dioxane and 30 mL of water was stirred at 80° C. overnight. Thereaction mixture was poured into water (200 mL) and extracted with EtOAc(200 mL). The organic layer was washed with water and brine, dried overNa₂SO₄, concentrated and purified by silica gel column (PE/EA=60/1) togive tert-butyl 4-(2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate(4.5 g, yield: 68%) as a yellow oil. MS: m/z 204.9 (M+H⁺).

A mixture of tert-butyl4-(2-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (3.1 g, 15.2mmol), wet 10% Pd/C (0.6 g) and MeOH (35 mL) was stirred at 40° C. under50 psi of H₂ overnight. The reaction mixture was filtered to give asolution of tert-butyl 4-(2-aminophenyl)piperidine-1-carboxylate usedfor next step directly. MS: m/z 177.0 (M+H⁺).

To the solution of tert-butyl 4-(2-aminophenyl)piperidine-1-carboxylatein MeOH (70 mL) was added HCHO (38% in H₂O, 7 mL), followed byNaBH(AcO)₃ (6.4 g, 30.2 mmol) and NaBH₃CN (4.8 g, 76 mmol). The solutionwas stirred at RT overnight. The resulting solution was poured into sat.NaHCO₃ solution (100 mL) and the aqueous phase was extracted with EtOAc(100 mL). The organic layer was washed with water and brine, dried overNa₂SO₄, concentrated and purified by silica gel column (PE/EA=15/1) togive tert-butyl 4-(2-(dimethylamino)phenyl)piperidine-1-carboxylate (1.5g, yield: 33% over 2 steps) as a white solid. MS: m/z 305.0 (M+H⁺).

To a solution tert-butyl4-(2-(dimethylamino)phenyl)piperidine-1-carboxylate (1.5 g, 4.93 mmol)in EA (15 mL) was added HCl/dioxane (5M, 15 mL) and the mixture wasstirred at room temperature for 2 hours. The reaction solution wasconcentrated to give HCl salt of N,N-dimethyl-2-(piperidin-4-yl) aniline(1.2 g, yield: 88%) as a white solid. MS: m/z 204.8 (M+H⁺).

A mixture of N,N-dimethyl-2-(piperidin-4-yl)aniline (600 mg, 2.16 mmol),6-bromo-2-cyclopropylquinazolin-4-ol (530 mg, 2.0 mmol), BOP (1.33 g,3.0 mmol) and DBU (1.2 g, 8 mmol) in MeCN (50 mL) was stirred at roomtemperature overnight. The reaction mixture was filtered and the cakewas dried to afford 2-(1-(6-bromo-2-cyclopropylquinazolin-4-yl)piperidin-4-yl)-N,N-dimethylaniline (730 mg, yield: 81%) as a whitesolid. ¹HNMR (300 MHz, CDCl₃): δ=7.98 (d, J=1.8 Hz, 1H), 7.74-7.64 (m,2H), 7.28-7.07 (m, 4H), 4.42-4.37 (m, 2H), 3.53-3.48 (m, 1H), 3.27-3.18(m, 2H), 2.70 (s, 6H), 2.21-2.15 (m, 1H), 1.92-1.86 (m, 4H), 1.21-1.16(m, 2H), 1.03-0.97 (m, 2H).

The title compound was prepared as described for2-({4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-amino)-ethanolfor the last three steps. ¹H NMR (300 MHz, CDCl₃): δ=7.83 (d, J=6.0 Hz,1H), 7.40 (d, J=2.7 Hz, 1H), 7.30-7.11 (m, 4H), 6.98 (d, J=3.0 Hz, 1H),4.46 (d, J=12.9 Hz, 2H), 3.88 (t, J=5.7 Hz, 2H), 3.59-3.49 (m, 3H),3.23-3.15 (m, 2H), 3.06 (s, 3H), 2.71 (s, 6H), 2.32-2.28 (m, 1H),1.95-1.77 (m, 4H), 1.27-1.17 (m, 2H), 1.05-1.00 (m, 2H). MS: m/z 446.3(M+H⁺).

Example 11: Preparation of{2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2-methoxy-ethyl)-methyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=8.31-8.28 (m, 1H), 7.35 (dd, J=9.3, 2.4 Hz,1H), 7.25-7.18 (m, 3H), 7.13-7.08 (m, 1H), 6.90 (d, J=2.7 Hz, 1H),4.82-4.78 (m, 2H), 3.63-3.58 (m, 5H), 3.40-3.31 (m, 5H), 3.05 (s, 3H),2.79-2.78 (m, 1H), 2.69 (s, 6H), 2.02-1.83 (m, 4H), 1.25-1.18 (m, 4H).MS: m/z 460.3 (M+H⁺).

Example 12: Preparation of{2-Cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=8.32-8.30 (m, 1H), 7.37-7.10 (m, 5H), 6.80(d, J=2.4 Hz, 1H), 4.80-4.75 (m, 2H), 3.70-3.55 (m, 7H), 3.36-3.31 (m,2H), 3.05 (s, 3H), 2.77-2.70 (m, 7H), 2.58-2.48 (m, 6H), 2.02-1.85 (m,4H), 1.28-1.18 (m, 4H). MS: m/z 515.4 (M+H⁺).

Example 13: Preparation of{2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.01-7.98 (m, 1H), 7.32 (dd, J=9.2, 2.4 Hz,1H), 7.24-7.16 (m, 3H), 7.11-7.07 (m, 1H), 6.94 (s, 1H), 4.55-4.51 (m,2H), 3.86-3.84 (m, 2H), 3.58-3.52 (m, 1H), 3.33-3.27 (m, 2H), 3.08 (s,3H), 3.01-2.90 (m, 4H), 2.74 (s, 6H), 2.45-2.42 (m, 1H), 2.02-1.82 (m,10H), 1.26-1.17 (m, 2H), 1.08-1.06 (m, 2H). MS: m/z 499.3 (M+H⁺).

Example 14: Preparation ofN-{2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-N,N′,N′-trimethyl-ethane-1,2-diamine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.93 (m, 1H), 7.31 (dd, J=10.0, 3.2 Hz, 1H),7.26-7.16 (m, 3H), 7.10 (t, J=7.6 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H),4.50-4.47 (m, 2H), 3.58-3.52 (m, 3H), 3.24-3.18 (m, 2H), 3.04 (s, 3H),2.70 (s, 6H), 2.55-2.51 (m, 2H), 2.32 (s, 6H), 1.93-1.88 (m, 4H),1.18-1.17 (m, 2H), 1.04-1.01 (m, 2H). MS: m/z 473.3 (M+H+).

Example 15: Preparation of2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described in example2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.89 (d, J=9.2 Hz, 1H), 7.40 (dd, J=9.2 Hz,1H), 7.26-7.20 (m, 2H), 6.98-6.94 (m, 2H), 6.89 (d, J=8.4 Hz, 1H), 4.35(d, J=12.8 Hz, 2H), 3.89-3.85 (m, 5H), 3.57 (t, J=5.6 Hz, 2H), 3.31-3.25(m, 1H), 3.17-3.06 (m, 5H), 1.98-1.84 (m, 4H), 1.61-1.47 (m, 4H). MS:m/z 451.2 (M+H⁺).

Example 16: Preparation of{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2-methoxy-ethyl)-methyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.87 (d, J=9.2 Hz, 1H), 7.36 (dd, J=9.2 Hz,1H), 7.26-7.20 (m, 2H), 6.98-6.88 (m, 3H), 4.35 (d, J=12.8 Hz, 2H), 3.85(s, 3H), 3.60 (s, 4H), 3.36 (s, 3H), 3.30-3.25 (m, 1H), 3.15-3.07 (m,5H), 1.97-1.84 (m, 4H), 1.53-1.44 (m, 4H). MS: m/z 465.2 (M+H⁺).

Example 17: Preparation of{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

¹H NMR (400 MHz, CDCl₃): δ=7.87 (d, J=9.2 Hz, 1H), 7.34 (dd, J=9.2 Hz,1H), 7.26-7.20 (m, 2H), 6.96 (t, J=7.6 Hz, 1H), 6.90-6.86 (m, 2H), 4.33(d, J=13.2 Hz, 2H), 3.85 (s, 3H), 3.69 (t, J=4.4 Hz, 1H), 3.58 (s, J=7.2Hz, 3H), 3.31-3.25 (m, 1H), 3.15-3.05 (m, 5H), 2.59-2.51 (m, 6H),1.97-1.85 (m, 4H), 1.53-1.46 (m, 4H). MS: m/z 520.3 (M+H⁺).

Example 18: Preparation of{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-dimethyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.90 (dd, J=10.0 Hz, 1H), 7.40 (dd, J=9.2 Hz,1H), 7.26-7.20 (m, 2H), 6.96 (t, J=7.6 Hz, 1H), 6.90-6.88 (m, 2H), 4.36(d, J=12.8 Hz, 2H), 3.85 (s, 3H), 3.57 (t, J=5.6 Hz, 2H), 3.32-3.24 (m,1H), 3.16-3.08 (m, 2H), 3.05 (s, 6H), 1.98-1.84 (m, 4H), 1.63-1.44 (m,4H). MS: m/z 421.2 (M+H⁺).

Example 19: Preparation of{2-(1-dimethylamino-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-dimethyl-amine

The title compound was prepared as a byproduct of{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-dimethyl-amine.¹H NMR (400 MHz, CD₃OD): δ=7.96-7.92 (m, 3H), 7.19 (d, J=7.2 Hz, 1H),7.09 (t, J=7.8 Hz, 1H), 6.86-6.76 (m, 3H), 6.47 (s, 1H), 5.02-5.94 (m,2H), 4.36 (s, 2H), 3.75 (s, 3H), 3.71-3.65 (m, 2H), 3.53-3.44 (m, 1H),3.20-3.18 (m, 8H), 2.87 (s, 6H), 2.05-2.03 (m, 4H). MS: m/z 446.3(M+H⁺).

Example 20: Preparation of{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.89 (d, J=8.4 Hz, 1H), 7.32 (dd, J=9.6 Hz,1H), 7.26-7.20 (m, 2H), 6.96 (t, J=7.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H),6.83 (d, J=3.2 Hz, 1H), 4.35 (d, J=12.8 Hz, 2H), 3.85 (s, 3H), 3.37 (t,J=7.4 Hz, 2H), 3.29-3.25 (m, 1H), 3.15-3.09 (m, 2H), 3.03 (s, 3H),1.98-1.88 (m, 4H), 1.67-1.60 (m, 2H), 1.55-1.47 (m, 4H), 0.95 (t, J=7.4Hz, 3H). MS: m/z 421.2 (M+H⁺).

Example 21: Preparation of{4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-[1-(methyl-propyl-amino)-cyclopropyl]-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as a byproduct of{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl-amine.¹H NMR (400 MHz, CD₃OD): δ=8.06-7.97 (m, 3H), 7.30-7.28 (m, 1H), 7.20(t, J=7.8 Hz, 1H), 6.98-6.84 (m, 3H), 6.58-6.55 (m, 1H), 5.11-5.08 (m,2H), 4.75 (d, J=13.2 Hz, 1H), 4.22 (d, J=10.8 Hz, 1H), 3.86 (s, 3H),3.81-3.72 (m, 2H), 3.60-3.51 (m, 3H), 3.34-3.16 (m, 7H), 2.90 (s, 3H),2.13 (s, 4H), 1.92-1.86 (m, 2H), 1.70-1.64 (m, 2H), 1.01-0.96 (m, 6H).MS: m/z 502.3 (M+H⁺).

Example 22: Preparation of2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.79-7.75 (m, 1H), 7.35-7.21 (m, 3H),7.00-6.89 (m, 3H), 4.34 (d, J=13.2 Hz, 2H), 3.87-3.85 (m, 5H), 3.56-3.53(m, 2H), 3.30-3.09 (m, 3H), 3.05 (s, 3H), 2.00-1.84 (m, 4H), 1.64 (s,3H), 1.43-1.40 (m, 2H), 0.82-0.81 (m, 2H). MS: m/z 447.3 (M+H⁺).

Example 23: Preparation ofN-[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.90 (brs, 1H), 7.27 (d, J=2.8 Hz, 1H),7.19-7.13 (m, 2H), 6.91-6.79 (m, 3H), 4.37 (d, J=12.8 Hz, 2H), 3.79 (s,3H), 3.59 (brs, 2H), 3.24-3.10 (m, 3H), 2.99 (s, 3H), 2.63-2.60 (m, 2H),2.36 (d, J=15.6 Hz, 6H), 1.95-1.80 (m, 4H), 1.60 (s, 3H), 1.42-1.38 (m,2H), 0.82-0.79 (m, 2H). MS: m/z 474.3 (M+H⁺).

Example 24: Preparation of[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.45 (brs, 1H), 7.37 (d, J=5.2 Hz, 1H), 7.36(s, 1H), 7.27-7.17 (m, 1H), 7.02-6.88 (m, 3H), 4.62 (d, J=13.6 Hz, 2H),4.03 (brs, 2H), 3.85 (s, 3H), 3.42-3.17 (m, 9H), 3.12 (s, 3H), 2.12(brs, 4H), 2.07-2.03 (m, 2H), 1.87-1.54 (m, 2H), 1.60 (s, 3H), 1.42-1.38(m, 2H), 0.82-0.79 (m, 2H). MS: m/z 500.3 (M+H⁺).

Example 25: Preparation of2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.92-7.82 (m, 1H), 7.38-7.11 (m, 5H), 7.00(s, 1H), 4.39 (d, J=13.2 Hz, 2H), 3.89-3.86 (m, 2H), 3.56-3.49 (m, 2H),3.20-3.12 (m, 2H), 3.06 (s, 3H), 2.71 (s, 6H), 2.11-1.65 (m, 4H), 1.63(s, 3H), 1.44-1.40 (m, 2H), 0.82-0.81 (m, 2H). MS: m/z 460.3 (M+H⁺).

Example 26: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-(2-methoxy-ethyl)-methyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.77 (d, J=9.3 Hz, 1H), 7.36-7.12 (m, 6H),6.94 (s, 1H), 4.35 (d, J=12.3 Hz, 2H), 3.61 (s, 4H), 3.50-3.48 (m, 1H),3.37 (s, 3H), 3.18-3.08 (m, 5H), 3.05 (s, 6H), 2.00-1.84 (m, 4H), 1.64(s, 3H), 1.43-1.40 (m, 2H), 0.82-0.81 (m, 2H). MS: m/z 474.3 (M+H⁺).

Example 27: Preparation of[4-[4-(2-dimethylamino-1-vinyl-propenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.77 (d, J=9.3 Hz, 1H), 7.34-7.11 (m, 6H),6.90 (brs, 1H), 4.33 (d, J=12.9 Hz, 2H), 3.73-3.70 (m, 4H), 3.61-3.50(m, 3H), 3.18-3.09 (m, 2H), 3.06 (s, 3H), 2.72 (s, 6H), 2.61-2.52 (m,6H), 2.30-2.24 (m, 1H), 1.99-1.92 (m, 4H), 1.64 (s, 3H), 1.45-1.41 (m,2H), 0.83-0.79 (m, 2H). MS: m/z 529.4 (M+H⁺).

Example 28: Preparation ofN-[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.79 (brs, 1H), 7.34-7.25 (m, 2H), 7.24-6.95(m, 3H), 6.82 (s, 1H), 4.28 (d, J=11.6 Hz, 2H), 3.53-3.39 (m, 3H),3.10-3.04 (m, 2H), 2.97 (s, 3H), 2.62 (d, J=12.8 Hz, 6H), 2.50 (brs,2H), 2.25 (d, J=19.6 Hz, 6H), 1.92-1.83 (m, 4H), 1.51 (s, 3H), 1.37-1.33(m, 2H), 0.77-0.73 (m, 2H). MS: m/z 487.3 (M+H⁺).

Example 29: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.67 (d, J=9.6 Hz, 1H), 7.27-7.01 (m, 5H),6.83 (s, 1H), 4.23 (d, J=12.4 Hz, 2H), 3.53-3.47 (m, 3H), 3.07-2.95 (m,5H), 2.70-2.50 (m, 12H), 2.00-1.72 (m, 8H), 1.55 (s, 3H), 1.35-1.31 (m,2H), 0.73-0.69 (m, 2H). MS: m/z 513.3 (M+H⁺).

Example 30: Preparation of:2-{[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=8.12 (brs, 1H), 7.39-7.35 (m, 1H), 7.21-7.14(m, 2H), 6.95-6.90 (m, 2H), 6.63 (d, J=8.1 Hz, 1H), 4.53 (d, J=14.1 Hz,2H), 3.98-3.93 (m, 5H), 3.59-3.55 (m, 2H), 3.22-3.13 (m, 3H), 3.06 (s,3H), 2.35-2.31 (m, 2H), 2.06-1.87 (m, 4H), 1.70 (s, 3H), 1.51-1.47 (m,2H), 0.89-0.87 (m, 2H). MS: m/z 472.3 (M+H⁺).

Example 31: Preparation of[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-(2-methoxy-ethyl)-methyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.77 (d, J=9.0 Hz, 1H), 7.36-7.15 (m, 3H),7.94-6.91 (m, 2H), 6.62 (d, J=8.1 Hz, 1H), 4.34 (d, J=12.9 Hz, 2H),3.99-3.94 (m, 4H), 3.61 (s, 4H), 3.38 (s, 3H), 3.11-3.02 (m, 6H),2.35-2.31 (m, 2H), 2.00-1.93 (m, 4H), 1.65 (s, 3H), 1.43-1.42 (m, 2H),0.82-0.81 (m, 2H). MS: m/z 486.3 (M+H⁺).

Example 32: Preparation of[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.77 (d, J=8.7 Hz, 1H), 7.34-7.14 (m, 3H),6.93-6.88 (m, 3H), 6.62 (d, J=8.1 Hz, 1H), 4.35-4.28 (m, 2H), 3.98-3.93(m, 4H), 3.73-3.70 (m, 4H), 3.60-3.56 (m, 4H), 3.11-2.98 (m, 6H),2.60-2.52 (m, 6H), 2.37- 2.28 (m, 2H), 2.03-1.88 (m, 4H), 1.64 (s, 3H),1.45-1.39 (m, 2H), 0.81-0.80 (m, 2H). MS: m/z 541.4 (M+H⁺).

Example 33: Preparation ofN-(2-methoxyethyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methyl-2-(1-methylcyclopropyl)quinazolin-6-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.91 (brs, 1H), 7.36-7.20 (m, 3H), 7.01-6.88(m, 3H), 4.41 (d, J=12.3 Hz, 2H), 3.87 (s, 3H), 3.61-3.58 (m, 4H), 3.37(s, 3H), 3.35-3.32 (m, 1H), 3.18-3.10 (m, 2H), 3.06 (s, 3H), 2.00-1.84(m, 4H), 1.64 (s, 3H), 1.43-1.40 (m, 2H), 0.82-0.81 (m, 2H). MS: m/z461.0 (M+H⁺).

Example 34: Preparation of4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methyl-2-(1-methylcyclopropyl)-N-(2-morpholinoethyl)quinazolin-6-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol¹H NMR (300 MHz, CDCl₃): δ=7.75 (d, J=9.0 Hz, 1H), 7.33-7.21 (m, 3H),7.00-6.90 (m, 3H), 4.33 (d, J=13.8 Hz, 2H), 3.87 (s, 3H), 3.72-3.69 (m,4H), 3.60-3.55 (m, 2H), 3.13-3.08 (m, 3H), 3.05 (s, 3H), 2.60-2.50 (m,6H), 1.97-1.89 (m, 4H), 1.65 (s, 3H), 1.42 (s, 2H), 0.82-0.79 (m, 2H),MS: m/z 516.0 (MAT).

Example 35: Preparation ofN-[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.77 (bs, 1H), 7.4-7.27 (m, 1H), 7.21-7.13(m, 2H), 6.90-6.87 (m, 2H), 6.61 (d, J=8 Hz, 1H), 4.35-4.31 (m, 2H),3.96-3.92 (m, 4H), 3.61-3.56 (m, 2H), 3.11-2.90 (m, 3H), 3.00 (s, 3H),2.59-2.56 (m, 1H), 2.35- 2.28 (m, 7H), 2.00-1.90 (m, 4H), 1.66-1.63 (m,2H), 1.45-1.39 (m, 2H), 0.81-0.80 (m, 2H). MS: m/z 499.3 (M+H⁺).

Example 36: Preparation of[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-(2-pyrrolidin-1-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.87 (d, J=8.7 Hz, 1H), 7.36-7.27 (m, 1H),7.21-7.14 (m, 2H), 6.92-6.87 (m, 2H), 6.63 (d, J=8.1 Hz, 1H), 4.39-4.33(m, 2H), 3.98-3.86 (m, 6H), 3.17-2.93 (m, 12H), 2.36-2.34 (m, 2H),2.07-1.64 (m, 8H), 1.61 (s, 3H), 1.45-1.43 (m, 2H), 0.83-0.81 (m, 2H).

Example 37: Preparation of{2-cyclopentyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-dimethyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.90 (brs, 1H), 7.30-7.28 (m, 1H), 7.24-7.21(m, 2H), 6.99-6.95 (m, 1H), 6.91-6.87 (m, 2H), 6.43-6.52 (m, 2H), 3.86(s, 3H), 3.46-3.28 (m, 4H), 3.04 (s, 6H), 2.12-1.70 (m, 12H). MS: m/z431.2 (M+H⁺).

Example 38: Preparation of2-({2-cyclopentyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.76 (d, J=8.8 Hz, 1H), 7.37-7.34 (m, 1H),7.25-7.20 (m, 2H), 6.98-6.89 (m, 3H), 4.44-4.39 (m, 2H), 3.89-3.86 (m,2H), 3.85 (s, 3H), 3.57-3.54 (m, 2H), 3.33-3.27 (m, 2H), 3.21-3.14 (m,2H), 3.05 (s, 3H), 2.12-1.73 (m, 10H), 1.70-1.63 (m, 2H). MS: m/z 461.2(M+H⁺)

Example 39: Preparation of{2-cyclopentyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2-methoxy-ethyl)-methyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.85 (brs, 1H), 7.38-7.36 (m, 1H), 7.25-7.23(m, 1H), 7.19-7.17 (m, 1H), 4.93-4.90 (brs, 2H), 3.87 (s, 3H), 3.80-3.70(m, 1H), 3.59-3.36 (m, 3H), 3.33 (s, 3H), 3.06 (s, 3H), 2.21-2.07 (m,4H), 1.97-1.60 (m, 11H). MS: m/z 475.3 (M+H⁺).

Example 40: Preparation of2-cyclopentyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.78-7.74 (m, 1H), 7.31-7.29 (m, 1H),7.28-7.20 (m, 2H), 6.99-6.85 (m, 3H), 4.41 (d, J=12.4 Hz, 2H), 3.84 (s,3H), 3.38-3.28 (m, 4H), 3.27-3.12 (m, 2H), 3.02 (s, 3H), 2.10-1.70 (m,10H), 1.69-1.61 (m, 4H), 0.95 (t, d, J=7.2 Hz, 3H). MS: m/z 459.3(M+H⁺).

Example 41: Preparation of2-cyclopentyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.83-7.75 (m, 1H), 7.33-7.30 (m, 1H),7.25-7.21 (m, 2H), 6.99-6.95 (m, 1H), 6.91-6.88 (m, 2H), 4.45-4.35 (m,2H), 3.86 (s, 3H), 3.70-3.68 (m, 4H), 3.59-3.55 (m, 2H), 333-3.30 (m,2H), 3.21-3.15 (m, 2H), 3.04 (s, 3H), 2.58-2.54 (m, 2H), 2.50 (bs, 4H),2.15-1.71 (m, 10H), 1.68-1.50 (m, 2H). MS: m/z 530.3 (M+H⁺).

Example 42: Preparation of{2-cyclobutyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-dimethyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.69 (d, J=9.2 Hz, 1H), 7.28-7.13 (m, 3H),6.92-6.82 (m, 3H), 4.39 (d, J=12.8 Hz, 2H), 3.79 (s, 3H), 3.70-3.66 (m,1H), 3.25-3.09 (m, 3H), 2.96 (s, 6H), 2.48-2.43 (m, 2H), 2.31-2.27 (m,2H), 1.99-1.88 (m, 6H). MS: m/z 417.2 (M+H⁺).

Example 43: Preparation of2-({2-cyclobutyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.67 (d, J=9.2 Hz, 1H), 7.26-7.20 (m, 3H),6.99-6.89 (m, 3H), 4.44 (d, J=12.4 Hz, 2H), 3.86-3.73 (m, 6H), 3.54-3.53(m, 2H), 3.31-3.16 (m, 3H), 3.04 (s, 3H), 2.54-2.49 (m, 2H), 2.35-2.33(m, 2H), 2.06-1.93 (m, 6H). MS: m/z 447.2 (M+H⁺).

Example 44: Preparation of2-cyclobutyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2-methoxy-ethyl)-methyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.71 (d, J=9.2 Hz, 1H), 7.28-7.27 (m, 1H),7.26-7.13 (m, 2H), 6.91-6.82 (m, 3H), 4.41 (d, J=12.8 Hz, 2H), 3.79 (m,3H), 3.76-3.68 (m, 1H), 3.67-3.54 (m, 1H), 3.52 (s, 3H), 3.28-3.25 (m,4H), 3.16-3.10 (m, 2H), 2.99 (s, 3H), 2.48-2.42 (m, 2H), 2.31-2.27 (m,2H), 1.99-1.87 (m, 6H). MS: m/z 461.3 (M+H⁺).

Example 45: Preparation of{2-cyclobutyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.75 (d, J=9.2 Hz, 1H), 7.31-7.21 (m, 3H),7.00-6.86 (m, 3H), 4.45 (d, J=13.6 Hz, 2H), 3.86 (s, 3H), 3.85-3.74 (m,1H), 3.38-3.30 (m, 3H), 3.21-3.16 (m, 2H), 3.02 (s, 3H), 2.55-2.50 (m,2H), 2.36-2.34 (m, 2H), 2.06-1.96 (m, 6H), 1.67-1.61 (m, 2H), 0.95 (t,3H). MS: m/z 445.3 (M+H⁺).

Example 46: Preparation of{2-cyclobutyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.76 (d, J=8.8 Hz, 1H), 7.28-7.27 (m, 1H),7.26-7.13 (m, 2H), 6.91-6.83 (m, 2H), 6.76 (s, 1H), 4.71 (d, J=11.6 Hz,2H), 3.94-3.92 (m, 1H), 3.80 (s, 3H), 3.77-3.62 (m, 4H), 3.61-3.48 (m,2H), 3.31-3.25 (m, 3H), 2.98 (s, 3H), 2.50-2.30 (m, 10H), 2.05-1.86 (m,6H). MS: m/z 516.3 (M+H⁺).

Example 47: Preparation of2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.81 (d, J=8.0 Hz, 1H), 7.39-7.36 (m, 1H),7.24-7.20 (m, 2H), 6.98-6.88 (m, 3H), 4.43 (d, J=12.0 Hz, 2H), 3.87 (s,3H), 3.86-3.85 (m, 2H), 3.57-3.55 (m, 2H), 3.31-3.16 (m, 3H), 3.06 (s,3H), 1.99-1.85 (m, 4H), 1.67-1.63 (m, 2H), 1.46-1.43 (m, 2H). MS: m/z501.2 (M+H⁺).

Example 48: Preparation of[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.80 (d, J=8.8 Hz, 1H), 7.40-7.10 (m, 3H),6.95-6.88 (m, 3H), 4.42 (d, J=13.8 Hz, 2H), 3.87 (s, 3H), 3.73-3.57 (m,6H), 3.61-3.48 (m, 2H), 3.32-3.14 (m, 3H), 3.06 (s, 3H), 2.62-2.49 (m,6H), 2.01-1.69 (m, 4H), 092-0.85 (m, 2H). MS: m/z 570.3 (M+H⁺).

Example 49: Preparation of2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described in example2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.77 (d, J=8.8 Hz, 1H), 7.39-7.39 (m, 1H),7.29-7.26 (m, 1H), 7.21-7.09 (m, 3H), 6.97 (s, 1H), 4.42 (d, J=13.2 Hz,2H), 3.88-3.85 (m, 2H), 3.58-3.50 (m, 3H), 3.22-3.17 (m, 2H), 3.06 (s,3H), 2.70 (s, 6H), 1.96-1.81 (m, 4H), 1.63 (bs, 2H), 1.45-1.43 (bs, 2H).MS: m/z 514.2 (M+H⁺).

Example 50: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.74 (d, J=8.0 Hz, 1H), 7.33-7.08 (m, 5H),6.87 (s, 1H), 4.39 (d, J=12.8 Hz, 2H), 3.70 (brs, 4H), 3.58-3.50 (m,3H), 3.20-3.14 (m, 2H), 3.05 (s, 3H), 2.70 (s, 6H), 2.59-2.51 (m, 6H),1.94-1.91 (m, 4H), 1.61-1.59 (m, 2H), 1.44-1.42 (m, 2H). MS: m/z 583.3(M+H⁺).

Example 51: Preparation of2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.40 (d, J=8.8 Hz, 1H), 7.25-7.20 (m, 3H),7.00-6.89 (m, 3H), 4.42 (d, J=13.8 Hz, 2H), 3.88-3.86 (m, 5H), 3.57-3.55(m, 2H), 3.20-3.10 (m, 3H), 3.05 (s, 3H), 3.06 (s, 3H), 2.42-2.40 (m,2H), 2.01-1.91 (m, 4H), 1.75-1.65 (m, 5H), 1.54-1.48 (m, 2H), 1.33-1.22(m, 4H). MS: m/z 475.3 (M+H⁺).

Example 52: Preparation of4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.34 (d, J=8.8 Hz, 1H), 7.25-7.15 (m, 3H),6.98-6.90 (m, 2H), 6.83-6.82 (m, 1H) 3.86 (s, 3H), 3.70-3.68 (m, 4H),3.59-3.57 (m, 2H), 3.56-3.28 (m, 3H), 3.05 (s, 3H), 2.57-2.40 (m, 8H),2.07-1.71 (m, 12H), 1.60-1.58 (m, 3H). MS: m/z 544.3 (M+H⁺).

Example 53: Preparation of{[4-[4-(2-Dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=8.30 (m, 1H), 7.38-7.35 (m, 1H), 7.19-7.14(m, 3H), 7.04-7.03 (m, 1H), 6.87 (bs, 1H), 4.84 (d, J=13.8 Hz, 2H), 3.80(bs, 2H), 3.58-3.50 (m, 3H), 3.38-3.36 (m, 2H), 3.00 (s, 3H), 2.63 (s,6H), 2.32-2.26 (m, 2H), 1.97-1.52 (m, 10H), 1.37 (s, 3H). MS: m/z 488.3(M+H⁺).

Example 54: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.45-7.35 (m, 2H), 7.23-7.18 (m, 4H), 6.88(bs, 1H), 5.00 (d, J=13.8 Hz, 2H), 3.79-3.69 (m, 10H), 3.07 (s, 3H),2.71-2.64 (m, 9H), 2.40-2.30 (m, 3H), 2.04-1.70 (m, 11H), 1.60 (s, 3H).MS: m/z 557.4 (M+H⁺).

Example 55: Preparation of2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.85 (d, J=9.2 Hz, 1H), 7.41-7.38 (m, 1H),7.23-7.20 (m, 2H), 6.98-6.88 (m, 3H) 4.43 (d, J=12.8 Hz, 2H), 3.88-3.87(m, 2H), 3.85 (s, 3H), 3.59-3.56 (m, 2H), 3.21-3.15 (m, 3H), 3H), 3.07(s, 3H), 2.86-2.83 (m, 2H), 2.24-2.20 (m, 2H), 1.96-1.90 (m, 4H),1.77-1.75 (m, 2H), 1.66-1.63 (m, 4H). MS: m/z 529.3 (M+H⁺).

Example 56: Preparation of[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.82 (d, J=8.8 Hz, 1H), 7.35-7.32 (m, 1H),7.23-7.20 (m, 2H), 6.98-6.88 (m, 3H) 4.40 (d, J=12.8 Hz, 2H), 3.85 (s,3H), 3.71-3.60 (m, 6H), 3.30-3.15 (m, 3H), 3.06 (s, 3H), 2.89-2.83 (m,2H), 2.58-2.52 (m, 5H), 2.24-2.17 (m, 2H), 1.97-1.91 (m, 4H), 1.77-1.75(m, 2H), 1.66-1.62 (m, 4H). MS: m/z 598.3 (M+H⁺).

Example 57: Preparation of2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.2 (bs, 1H), 7.46 (d, J=9.2 Hz, 1H),7.29-7.26 (m, 1H), 7.26-7.13 (m, 4H), 6.97 (s, 1H) 4.58 (d, J=12.8 Hz,2H), 3.88-3.86 (m, 2H), 3.61-3.59 (m, 3H), 3.34-3.32 (m, 2H), 3.13-3.11(m, 2H), 3.06 (s, 3H), 2.91-2.84 (m, 2H), 2.75 (s, 6H), 2.31-2.24 (m,2H), 1.94-1.92 (m, 2H), 1.79-1.78 (m, 2H), 1.69-1.66 (m, 2H). MS: m/z542.3 (M+H⁺).

Example 58: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.76 (d, J=9.2 Hz, 1H), 7.29-7.26 (m, 1H),7.25-7.02 (m, 4H), 6.83 (s, 1H) 4.33 (d, J=12.8 Hz, 2H), 3.65 (bs, 4H),3.55-3.45 (m, 3H), 3.16-3.10 (m, 2H), 3.00 (s, 3H), 2.82-2.76 (m, 2H),2.63 (s, 6H), 2.53-2.47 (m, 6H), 2.18-2.11 (m, 2H), 1.91-1.80 (m, 4H),1.70-1.68 (m, 2H), 1.59-1.56 (m, 2H). MS: m/z 611.3 (M+H⁺).

Example 59: Preparation of2-({2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.78 (d, J=9.6 Hz, 1H), 7.32-7.29 (m, 1H),7.19-7.14 (m, 2H), 6.91-6.82 (m, 3H), 4.39 (d, J=13.2 Hz, 2H), 3.82-3.80(m, 2H), 3.79 (s, 3H), 3.52-3.49 (m, 2H), 3.24-3.12 (m, 3H), 3.00 (s,3H), 2.81-2.76 (m, 2H), 2.60-2.54 (m, 2H), 1.97-1.83 (m, 6H). MS: m/z465.2 (M+H⁺).

Example 60: Preparation of{2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.89 (d, J=9.3 Hz, 1H), 7.38-7.20 (m, 3H),7.01-6.91 (m, 3H), 4.46 (d, J=12.6 Hz, 2H), 3.88 (s, 3H), 3.72-3.70 (m,4H), 3.63-3.58 (m, 2H), 3.34-3.18 (m, 3H), 3.08 (s, 3H), 2.91-2.87 (m,2H), 2.73-2.52 (m, 8H), 2.01-1.94 (m, 6H). MS: m/z 534.3 (M+H⁺).

Example 61:2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.83 (d, J=8.8 Hz, 1H), 7.37-7.10 (m, 5H),6.98 (s, 1H), 4.46 (d, J=12.4 Hz, 2H), 3.87 (brs, 2H), 3.59-3.53 (m,3H), 325-3.10 (m, 2H), 3.07 (s, 3H), 2.87-2.86 (m, 2H), 2.70 (s, 6H),2.64-2.62 (m, 2H), 2.01-1.94 (m, 6H). MS: m/z 478.3 (M+H⁺).

Example 62: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclobutyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.90 (d, J=9.2 Hz, 1H), 7.37-7.09 (m, 5H),6.91 (s, 1H), 4.46 (d, J=12.6 Hz, 2H), 3.76-3.52 (m, 7H), 3.26-3.20 (m,2H), 3.08 (s, 3H), 2.91-2.83 (m, 2H), 2.71 (s, 6H), 2.68-2.54 (m, 7H),2.00-1.94 (m, 7H). MS: m/z 547.4 (M+H⁺).

Example 63: Preparation of2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.86 (d, J=6.8 Hz, 1H), 7.43-7.40 (m, 1H),7.26-7.20 (m, 2H), 7.00-6.88 (m, 3H) 4.45 (d, J=13.2 Hz, 2H),3.3.88-3.87 (m, 2H), 3.85 (s, 3H), 3.60-3.57 (m, 2H), 3.33-3.18 (m, 3H),3.08 (s, 3H), 2.94-2.87 (m, 2H), 2.76-2.69 (m, 2H), 2.12-2.05 (m, 1H),1.96-1.73 (m, 5H). MS: m/z 515.2 (M+H⁺).

Example 64: Preparation of[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.83 (d, J=9.2 Hz, 1H), 7.36-7.33 (m, 1H),7.26-7.20 (m, 2H), 6.98-6.88 (m, 3H) 4.41 (d, J=12.8 Hz, 2H), 3.85 (s,3H), 3.71-3.70 (m, 4H), 3.61-3.58 (m, 2H), 3.31-3.15 (m, 3H), 3.07 (s,3H), 2.93-2.86 (m, 2H), 2.76-2.71 (m, 2H), 2.68-2.52 (m, 6H), 2.10-2.07(m, 1H), 1.97-1.91 (m, 5H). MS: m/z 584.3 (M+H⁺).

Example 65: Preparation of2-{[4-[4-(2-Dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.84 (d, J=9.6 Hz, 1H), 7.51-7.00 (m, 6H)4.42 (d, J=12.8 Hz, 2H), 3.92-3.87 (m, 2H), 3.64-3.52 (m, 3H), 3.28-3.24(m, 2H), 3.20 (s, 3H), 2.94-2.85 (m, 2H), 2.80-2.73 (m, 2H), 2.72 (s,6H), 2.25-1.80 (m, 6H). MS: m/z 528.3 (M+H⁺).

Example 66: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.84 (d, J=9.6 Hz, 1H), 7.37-7.34 (m, 1H),7.27-7.07 (m, 4H), 6.91 (s, 1H) 4.41 (d, J=12.8 Hz, 2H), 3.72-3.62 (m,4H), 3.60-3.50 (m, 3H), 3.22-3.17 (m, 2H), 3.07 (s, 3H), 2.94-2.87 (m,2H), 2.76-2.73 (m, 2H), 2.72 (s, 6H), 270-2.49 (m, 6H), 2.10-1.86 (m,6H). MS: m/z 597.3 (M+H⁺).

Example 67: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol. ¹H NMR (400 MHz,DMSO-d₆): δ=7.64 (d, J=8.8 Hz, 1H), 7.44-7.41 (m, 1H), 7.29-7.28 (m,1H), 7.18-7.17 (m, 2H), 7.07-7.03 (m, 1H), 6.84 (s, 1H), 4.30 (d, J=12.8Hz, 2H), 3.60-3.43 (m, 7H), 3.33-3.02 (m, 5H), 2.68-2.61 (m, 9H),2.50-2.42 (m, 4H), 2.01-1.78 (m, 8H), 1.54 (s, 3H). MS: m/z 543.4(M+H⁺).

Example 68: Preparation of2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.64 (d, J=8.8 Hz, 1H), 7.44-7.41 (m, 1H),7.24-7.14 (m, 2H), 7.00-6.93 (m, 2H), 6.81 (s, 1H), 3.88-3.84 (m, 2H),3.64-3.49 (m, 3H), 3.39-3.34 (m, 2H), 3.07 (s, 3H), 2.80-2.73 (m, 2H),2.68-2.64 (m, 6H), 2.21- 1.50 (m, 10H), 1.25 (s, 3H), 0.90-0.81 (m, 2H).MS: m/z 474.3 (M+H+).

Example 69: Preparation of[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, DMSO-d₆): δ=7.64 (d, J=8.8 Hz, 1H), 7.44-7.41 (m, 1H),7.24-7.14 (m, 2H), 7.00-6.93 (m, 2H), 6.81 (s, 1H), 4.30 (d, J=11.6 Hz,2H), 3.81 (s, 3H), 3.59-3.51 (m, 6H), 3.30-3.07 (m, 3H), 3.02 (s, 3H),2.67-2.60 (m, 2H), 1.95-1.81 (m, 6H), 1.53 (s, 3H). MS: m/z 530.3(M+H⁺).

Example 70: Preparation of2-{[4-[4-(2-Methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, DMSO-d₆): δ=7.63 (d, J=8.8 Hz, 1H), 7.45-7.41 (m, 1H),7.25-7.18 (m, 2H), 7.00-6.91 (m, 2H), 6.82 (s, 1H), 4.74-4.72 (m, 1H),4.32 (d, J=11.6 Hz, 2H), 3.81 (s, 3H), 3.60-3.58 (m, 2H), 3.51-3.48 (m,2H), 3.12-3.09 (m, 3H), 3.03 (s, 3H), 2.67-2.61 (m, 4H), 2.01-1.80 (m,6H), 1.54 (s, 3H). MS: m/z 461.3 (M+H⁺).

Example 71: Preparation of{2-(1fluoro-cyclopentyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.91 (d, J=8.8 Hz, 1H), 7.35-7.32 (m, 1H),7.26-7.20 (m, 2H), 6.96-6.89 (m, 3H) 4.49 (d, J=12.8 Hz, 2H), 3.85 (s,3H), 3.71-3.60 (m, 6H), 3.30-3.15 (m, 3H), 3.06 (s, 3H), 2.61-2.57 (m,2H), 2.49-2.40 (m, 4H), 2.38-2.02 (m, 4H), 2.01-1.89 (m, 8H). MS: m/z548.3 (M+H+).

Example 72: Preparation of2-({2-(1-fluoro-cyclopentyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.94 (d, J=8.8 Hz, 1H), 7.35-7.29 (m, 1H),7.26-7.21 (m, 2H), 6.99-6.89 (m, 3H) 4.47 (d, J=12.8 Hz, 2H), 3.89-3.85(m, 5H), 3.60-3.57 (m, 2H), 3.32-3.18 (m, 3H), 3.06 (s, 3H), 2.61-2.57(m, 2H), 2.49-2.40 (m, 4H), 2.38-2.02 (m, 4H), 2.01-1.89 (m, 8H). MS:m/z 479.3 (M+H+).

Example 73: Preparation of[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclopentyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.91 (d, J=12.8 Hz, 1H), 7.33-7.08 (m, 5H),6.90 (s, 1H), 4.41 (d, J=12.8 Hz, 2H), 3.72-3.60 (m, 4H), 3.58-3.50 (m,3H), 3.22-3.15 (m, 2H), 3.07 (s, 3H), 2.68 (s, 6H), 2.61-2.57 (m, 2H),2.52-2.25 (m, 8H), 2.01-1.87 (m, 8H). MS: m/z 561.4 (M+H⁺).

Example 74: Preparation of{2-cyclopentyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.81 (brs, 1H), 7.33-7.32 (m, 2H), 7.26-7.21(m, 2H), 7.12-7.09 (m, 1H), 6.92 (s, 1H) 4.40-4.37 (m, 2H), 3.70-3.68(m, 4H), 3.60-3.57 (m, 3H), 3.20-3.14 (m, 2H), 3.06 (s, 3H), 2.95-2.91(m, 2H), 2.70 (s, 6H), 2.60-2.56 (m, 2H), 2.52-2.51 (m, 5H), 2.10-1.92(m, 6H), 1.57 (m, 4H). MS: m/z 541.3 (M+H⁺).

Example 75: Preparation of2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.96 (d, J=9.2 Hz, 1H), 7.44-7.40 (m, 1H),7.28 (s, 1H), 7.21-7.19 (m, 2H), 7.12 (s, 1H), 7.10 (s, 1H), 4.33 (d,J=12.8 Hz, 2H), 3.90-3.87 (m, 2H), 3.61-3.49 (m, 3H), 3.30-3.20 (m, 2H),3.08 (s, 3H), 2.78 (s, 6H), 2.53-2.20 (m, 4H), 2.02-1.88 (m, 8H). MS:m/z 492.3 (M+H+).

Example 76: Preparation of1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol

The mixture of 2-amino-5-bromo-benzoic acid ethyl ester (3.0 g, 13.16mmol) and cyclopropanecarbonitrile (2.6 g, 39.47 mmol) in 6 MHCl/dioxane (60 mL) was stirred at reflux overnight. The solid wasfiltered, dried in vacuum to give 6-bromo-2-cyclopropyl-quinazolin-4-ol(3.3 g, yield: 95%) as crude product. MS: m/z 249.1 (M+H⁺).

A mixture of 6-bromo-2-cyclopropyl-quinazolin-4-ol (3.3 g, 13.16 mmol),4-(2-methoxy-phenyl)-piperidine hydrochloride (3.3 g, 14.48 mmol), DBU(8.0 g, 52.64 mmol), and BOP (8.7 g, 19.47 mmol) in ACN (30 mL) wasstirred at 25° C. overnight. The mixture was partitioned between water(60 mL) and EtOAc (60 mL). The aqueous phase was extracted with EtOAc(40 mL×2). The extracts were dried over Na₂SO₄, and concentrated todryness. The residue was purified by silica gel column chromatography(PE/EA=10/1) to afford6-bromo-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(4.2 g, yield: 73%) as a white solid. ¹H NMR (400 HMz, CDCl₃): δ=7.97(s, 1H), 7.72-7.64 (m, 2H), 7.23-7.20 (m, 1H), 6.98-6.88 (m, 2H),4.40-4.36 (m, 2H), 3.86 (s, 3H), 3.30-3.19 (m, 3H), 2.20-2.16 (m, 1H),1.98-1.77 (m, 4H), 1.20-1.16 (m, 2H), 1.03-0.98 (m, 2H).

To a mixture of6-bromo-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(100 mg, 0.237 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine (102mg, 0.474 mmol) and Cs₂CO₃ (154 mg, 0.474 mmol) in anhydrous toluene (20mL) was added BINAP (30 mg, 0.048 mmol) and Pd(OAc)₂ (5.0 mg, 0.024mmol). The mixture was refluxed under N₂ overnight. The mixture wasconcentrated under reduced pressure and the residue was partitionedbetween water (60 mL) and EtOAc (30 mL). The aqueous phase was extractedwith EtOAc (15 mL×2). The extracts were dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by Pre-TLC (PE/EA=5/1)to give6-[4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(100 mg, yield: 74%) as a pale yellow solid. MS: m/z 572.0 (M+H⁺).

To a solution of6-[4-(tert-butyl-dimethyl-silanyloxy)-piperidin-1-yl]-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(100 mg, 0.180 mmol) in MeOH (1 mL) was added conc.HCl (one drop), thereaction mixture was stirred at room temperature overnight. The mixturewas concentrated under reduced pressure. The residue was partitionedbetween water (30 mL) and EtOAc (30 mL). The aqueous phase was extractedwith EtOAc (20 mL×2). The extracts were dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by Pre-TLC(DCM/MeOH=10/1) to give1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol(40 mg, yield: 48%) as a yellow solid. ¹H NMR (400 HMz, CDCl₃):δ=7.73-7.71 (m, 1H), 7.48-7.45 (m, 1H), 7.26-7.21 (m, 2H), 7.11 (d,J=2.1 Hz, 1H), 6.99-6.97 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.36-4.33 (m,2H), 3.91-3.89 (m, 1H), 3.86 (s, 3H), 3.54-3.52 (m, 2H), 3.33-3.17 (m,3H), 3.00-2.97 (m, 2H), 2.30-2.27 (m, 1H), 2.07-1.72 (m, 9H), 1.18-1.16(m, 2H), 1.02-1.00 (m, 2H). MS: m/z 459.3 (M+H⁺).

Example 77: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(4-methoxy-piperidin-1-yl)-quinazoline

The title compound was prepared as described for1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol.¹HNMR (400 HMz, CDCl₃): δ=7.84-7.79 (m, 1H), 7.48-7.45 (m, 1H),7.24-7.21 (m, 2H), 7.10 (d, J=2.4 Hz, 1H), 6.99-6.96 (m, 1H), 6.90 (d,J=8.8 Hz, 1H), 4.43-4.38 (m, 2H), 3.86 (s, 3H), 3.55-3.50 (m, 2H),3.42-3.38 (m, 4H), 3.30-3.26 (m, 1H), 3.15 (t, J=12.4 Hz, 2H), 3.04-2.96(m, 2H), 2.10-2.23 (m, 1H), 2.06-1.74 (m, 8H), 1.17-1.15 (m, 2H),0.98-0.97 (m, 2H). MS: m/z 474.3 (M+H⁺).

Example 78:(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-dimethyl-amine

The title compound was prepared as described for1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol.¹H NMR (400 HMz, CDCl₃): δ=7.75-7.74 (m, 1H), 7.45 (dd, J=8.0, 0.8 Hz,1H), 7.23-7.21 (m, 2H), 7.11 (s, 1H), 6.99-6.96 (m, 1H), 6.90 (d, J=8.4Hz, 1H), 4.37-4.34 (m, 2H), 3.86 (s, 3H), 3.79-3.76 (m, 2H), 3.31-3.16(m, 3H), 2.81-2.75 (m, 2H), 2.43 (s, 6H), 2.22-2.20 (m, 1H), 2.08-1.70(m, 9H), 1.25-1.16 (m, 2H), 0.99-0.97 (m, 2H). MS: m/z 486.3 (M+H⁺).

Example 79: Preparation of1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol

The title compound was prepared as described for1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol.¹H NMR (400 HMz, CDCl₃): δ=7.84-7.83 (m, 1H), 7.26-7.21 (m, 2H), 7.06(dd, J=9.6, 2.0 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 6.90 (dd, J=8.4, 3.2Hz, 1H), 6.65 (s, 1H), 4.68-4.66 (m, 1H), 4.48-4.4.46 (m, 2H), 3.86 (s,3H), 3.60-3.55 (m, 2H), 3.43-3.28 (m, 3H), 3.19-3.13 (m, 2H), 2.34-2.32(m, 1H), 2.24-1.81 (m, 8H), 1.02-1.01 (m, 2H), 1.01-0.99 (m, 2H). MS:m/z 445.3 (M+H⁺).

Example 80: Preparation of2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)-quinazoline

The title compound was prepared as described for1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol.¹H NMR (400 HMz, CDCl₃): δ=7.68-7.66 (m, 1H), 7.19-7.13 (m, 2H), 7.07(dd, J=8.8, 2.1 Hz, 1H), 6.90 (t, J=7.6 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H),6.62 (s, 1H), 4.32-4.29 (m, 2H), 4.08-4.06 (m, 1H), 3.79 (s, 3H),3.51-3.37 (m, 3H), 3.36 (s, 3H), 3.22-3.19 (m, 1H), 3.08-3.01 (m, 2H),2.13-2.06 (m, 2H), 1.92-1.77 (m, 6H), 1.10-1.06 (m, 2H), 0.91-0.87 (m,2H). MS: m/z 459.2 (M+H⁺).

Example 81: Preparation of(R)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol,HCl salt

The title compound was prepared as described for1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol.¹H NMR (400 HMz, CD₃OD): δ=7.62 (d, J=8.8 Hz, 1H), 7.42-7.39 (m, 1H),7.21 (d, J=7.6 Hz, 2H), 7.00-6.90 (m, 3H), 5.03-5.00 (m, 2H), 4.62-4.60(m, 1H), 3.88 (s, 3H), 3.52-3.37 (m, 6H), 3.60-3.51 (m, 6H), 2.26-2.23(m, 1H), 2.18-2.09 (m, 4H) 1.97- 1.91 (m, 2H), 1.37-1.29 (m, 4H). MS:m/z 445.2 (M+H⁺).

Example 82: Preparation of(S)-1-(2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)pyrrolidin-3-ol

The title compound was prepared as described for2-({2-cyclopropyl-4-[3-(2-methoxy-phenylamino)-pyrrolidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 HMz, CD₃OD): δ=7.49 (dd, J=9.2, 1.8 Hz, 1H), 7.29-7.24 (m,1H), 7.13-7.07 (m, 2H), 6.88-6.74 (m, 3H), 4.88 (d, J=12.4 Hz, 2H),4.50-4.48 (m, 1H), 3.74 (s, 3H), 3.53-3.34 (m, 6H), 2.14-1.94 (m, 5H),1.82-1.77 (m, 2H), 1.26-1.15 (m, 2H). MS: m/z 445.2 (M+H⁺).

Example 83: Preparation of(R)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline,HCl salt

The title compound was prepared as described for2-({2-cyclopropyl-4-[3-(2-methoxy-phenylamino)-pyrrolidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹HNMR (400 HMz, CD₃OD): δ=7.52 (d, J=8.8 Hz, 1H), 7.18-7.05 (m, 3H),6.86-6.78 (m, 2H), 6.65 (d, J=2.4 Hz, 1H), 4.36 (d, J=14.0 Hz, 2H),4.09-4.06 (m, 1H), 3.84 (s, 3H), 3.50-3.35 (m, 1H), 3.40-3.20 (m, 7H),3.11-3.00 (m, 2H), 2.12-1.96 (m, 3H), 1.85-1.78 (m, 4H), 1.07 (m, 2H),0.92-0.85 (m, 2H). MS: m/z 459.2 (M+H⁺)

Example 84: Preparation of(S)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline

The title compound was prepared as described for2-({2-cyclopropyl-4-[3-(2-methoxy-phenylamino)-pyrrolidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 HMz, CD₃OD): δ=7.49 (d, J=9.2 Hz, 1H), 7.26 (dd, J=9.2, 2.4Hz, 1H), 7.12-7.08 (m, 2H), 6.88-6.74 (m, 3H), 4.89-4.83 (m, 2H),4.10-4.07 (m, 1H), 3.75 (s, 3H), 3.50-3.32 (m, 7H), 3.28 (s, 3H),2.20-1.93 (m, 5H), 1.85-1.78 (m, 2H), 1.24-1.12 (m, 4H). MS: m/z 459.2(M+H⁺)

Example 85: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl-propyl-amine

To a mixture of6-bromo-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(1.09 g, 2.5 mmol) in THF (25 mL) at −78° C. was added n-BuLi (1 mL, 2.5mmol). The resulting mixture was stirred at −78° C. for 2 hours. ThenDMF (0.4 mL, 5.0 mmol) was added into the mixture. The reaction mixturewas allowed to warm to room temperature and stirred for another 2 hours.The mixture was partitioned between NH₄Cl (aq. 50 mL) and EtOAc (50 mL).The aqueous phase was extracted with EtOAc (50 mL×2). The extracts werewashed with water (100 mL×2), brine (100 mL), and dried over Na₂SO₄. Thesolution was concentrated to dryness and the residue was purified bysilica gel column chromatography (PE/EA=10/1) to afford2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline-6-carbaldehyde(600 mg, yield: 73%) as a pale yellow solid. ¹H NMR (400 HMz, CDCl₃):δ=9.96 (s, 1H), 9.26 (d, J=1.2 Hz, 1H), 8.03 (dd, J=8.8, 1.6 Hz, 1H),7.76 (d, J=8.8 Hz, 1H), 7.17-7.13 (m, 2H), 6.89 (t, J=7.2 Hz, 1H), 6.83(d, J=8.0 Hz, 1H), 4.51-4.48 (m, 2H), 3.79 (s, 3H), 3.29-3.23 (m, 2H),2.15-2.10 (m, 1H), 1.97-1.80 (m, 5H), 1.16-1.13 (m, 2H), 1.00-0.97 (m,2H). MS: m/z 388.3 (M+H⁺).

To a mixture of2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline-6-carbaldehyde(80 mg, 0.21 mmol) in DCM (8 mL) was added propylamine (29 mg, 0.42mmol) and HOAc (one drop). The mixture was stirred at 30° C. overnight.Then Na(OAc)₃BH (219 mg, 1.04 mmol) and NaBH₄ (39 mg, 1.04 mmol) wereadded and the resulting mixture was stirred at 30° C. overnight again.The mixture was partitioned between water (30 mL) and DCM (30 mL). Theaqueous phase was extracted with DCM (30 mL×2). The extracts were washedwith water (50 mL×2), dried over Na₂SO₄, The solution was concentratedto dryness give{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-propyl-amine(89 mg, yield: 98%) as a colorless oil. MS: m/z 431.3 (M+H⁺).

To a mixture of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-propyl-amine(89 mg, 0.21 mmol) in MeOH (5 mL), was added HCHO (3 mL) and HOAc (onedrop). The resulting mixture was stirred for 1 hour at room temperature.Then Na(OAc)₃BH (87 mg, 0.41 mmol) and NaBCNH₃ (64 mg, 1.03 mmol) wereadded and the resulting mixture was stirred at room temperatureovernight again. The mixture was partitioned between water (30 mL) andEtOAc (30 mL). The aqueous phase was extracted with EtOAc (30 mL×2). Theextracts were washed with water (50 mL×2), and brine (50 mL) and driedover Na₂SO₄. The solution was concentrated and purified by Prep-TLC(DCM/MeOH=10/1), lyophilized with 2N HCl to afford{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl-propyl-amine(40 mg, yield: 43%) as a white solid. ¹H NMR (400 HMz, CD₃OD): δ=8.26(s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.13-7.09 (m,2H), 6.87 (d, J=7.6 Hz, 1H), 6.81 (t, J=7.6 Hz, 1H), 4.57 (d, J=12.8 Hz,1H), 4.36 (d, J=12.8 Hz, 1H), 3.75 (s, 3H), 3.44-3.38 (m, 2H), 6.89 (t,J=14.8 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 5.15-4.78 (m, 2H), 4.55 (d,J=13.2 Hz, 1H), 4.38 (d, J=13.2 Hz, 1H), 3.75 (s, 3H), 3.73-3.22 (m,3H), 3.13-3.08 (m, 1H), 3.04-3.01 (m, 1H), 2.72 (s, 3H), 2.12-2.10 (m,1H), 2.02-1.99 (m, 2H), 1.85-1.73 (m, 4H), 1.33- 1.27 (m, 4H), 0.92 (t,J=7.2 Hz, 3H). MS: m/z 445.3 (M+H⁺).

Example 86: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-dimethyl-amine

The title compound was prepared as described for{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl-propyl-amine.¹H NMR (400 HMz, CD₃OD): δ=8.28 (s, 1H), 7.99 (dd, J=8.4, 1.2 Hz, 1H),7.71 (d, J=8.8 Hz, 1H), 7.13-7.08 (m, 2H), 6.88-6.79 (m, 2H), 4.59 (s,2H), 3.76 (s, 3H), 3.41-3.40 (m, 1H), 3.22-3.20 (m, 4H), 2.80 (s, 6H),2.13-2.10 (m, 1H), 2.02-2.00 (m, 2H), 1.87-1.83 (m, 2H), 1.32-1.26 (m,4H). MS: m/z 417.2 (M+H⁺).

Example 87: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-(2-methoxy-ethyl)-methyl-amine

The title compound was prepared as described for{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl-propyl-amine.¹H NMR (400 HMz, CD₃OD): δ=8.25 (s, 1H), 8.01-7.80 (m, 1H), 7.71 (d,J=8.8 Hz, 1H), 7.12-7.08 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.81 (t, J=7.6Hz, 1H), 4.57 (d, J=13.2 Hz, 1H), 4.43 (d, J=13.2 Hz, 1H), 3.75 (s, 3H),3.68 (t, J=6.8 Hz, 2H), 3.42-3.38 (m, 3H), 3.35 (s, 3H), 3.34-3.21 (m,3H), 2.81 (s, 3H), 2.12-2.11 (m, 1H), 2.03-1.99 (m, 2H), 1.85-1.83 (m,2H), 1.33-1.26 (m, 4H). MS: m/z 461.3 (M+H⁺).

Example 88: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl-propyl-amine.¹H NMR (400 HMz, CD₃OD): δ=8.43 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.69(d, J=8.4 Hz, 1H), 7.16-7.09 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (t,J=7.6 Hz, 1H), 3.94-3.89 (m, 6H), 3.81 (s, 3H), 3.80-3.40 (m, 7H),3.22-3.20 (m, 5H), 2.80 (s, 3H), 2.12-2.11 (m, 1H), 2.03-2.00 (m, 2H),1.89-1.88 (m, 2H), 1.33-1.26 (m, 4H). MS: m/z 516.3 (M+H⁺).

Example 89: Preparation of2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl-amino)-ethanol

The title compound was prepared as described for{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl-propyl-amine.¹H NMR (400 HMz, CD₃OD): δ=8.37 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.82(d, J=8.8 Hz, 1H), 7.25-7.21 (m, 2H), 7.00 (d, J=6.8 Hz, 1H), 6.93 (t,J=6.8 Hz, 1H), 5.09-5.01 (m, 2H), 4.72-4.71 (m, 1H), 4.58-4.54 (m, 1H),3.95 (t, J=4.8 Hz, 2H), 3.87 (s, 3H), 3.56-3.50 (m, 5H), 2.96 (s, 3H),2.23-2.21 (m, 1H), 2.15-2.12 (m, 2H), 1.97-1.94 (m, 2H), 1.45-1.37 (m,4H). MS: m/z 447.3 (M+H⁺).

Example 90: Preparation of({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-aceticacid ethyl ester

A mixture of 2-cyclopropyl-6-nitro-quinazolin-4-ol (500 mg, 2.32 mmol),4-(2-methoxy-phenyl)-piperidine hydrochloride (581 mg, 2.55 mmol), DBU(1.41 g, 9.260 mmol), and BOP (1.54 g, 3.47 mmol) in ACN (5 mL) wasstirred at 25° C. overnight. The mixture was partitioned between water(30 mL) and EtOAc (30 mL), extracted with EtOAc (20 mL×2), dried overNa₂SO₄, The solution was concentrated to dryness and the residue waspurified silica gel column chromatography (PE/EA=10/1) to afford2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-nitro-quinazoline(520 mg, yield: 56%) as a yellow solid. MS: m/z 405.3 (M+H⁺).

To a mixture of2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-nitro-quinazoline(260 mg, 0.642 mmol) in MeOH (10 mL), was added Pd/C (10% wet, 80 mg)under N₂. The suspension was degassed under reduced pressure and purgedwith N₂ atmosphere several times. The resulting mixture was stirredovernight at room temperature. The solvent was concentrated afterfiltration, dried in vacuo to give2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylamine(240 mg, yield: 100%) as a yellow solid.

To a solution of2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylamine(160 mg, 0.42 mmol) in DMF (10 mL), was added bromo-acetic acid ethylester (142 mg, 0.85 mmol) and K₂CO₃ (235 mg, 1.70 mmol). The reactionmixture was stirred at 100° C. for overnight. The mixture waspartitioned between water (50 mL) and EtOAc (50 mL), extracted withEtOAc (50 mL×2), the organic layer was dried over Na₂SO₄, The solutionwas concentrated to dryness and the residue was purified silica gelcolumn chromatography (PE/EA=10/1) (DCMMeOH=20/1) to give{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylamino}-aceticacid ethyl ester (170 mg, yield: 87%) as a yellow solid. MS: m/z 461.3(M+H⁺).

To a mixture of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylamino}-aceticacid ethyl ester (170 mg, 0.36 mmol) in MeOH (10 mL), was added HCHO (5mL) and HOAc (one drop), The resulting mixture was stirred for 1 hour atroom temperature. Then Na(OAc)₃BH (391 mg, 1.85 mmol) and NaBCNH₃ (114mg, 1.85 mmol). The resulting mixture was stirred for overnight roomtemperature. The solvent was removed under reduced pressure and theresidue was partitioned between water (30 mL) and EtOAc (30 mL),extracted with EtOAc (30 mL×2), washed the organic layers with water (50mL×2) and brine (50 mL×1), dried over Na₂SO₄, The solution wasconcentrated to dryness and the residue was purified by Prep-HPLC,lyophilized with 2N HCl to afford({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-aceticacid ethyl ester (25.8 mg, yield: 15%) as a yellow solid. ¹H NMR (300HMz, CD₃OD): δ=7.62 (d, J=9.3 Hz, 2H), 7.54 (dd, J=9.0, 2.4 Hz, 2H),7.02-6.93 (m, 3H), 4.97-4.91 (m, 2H), 4.34 (s, 2H), 4.15 (q, J=6.9 Hz,2H), 3.87 (s, 3H), 3.52-3.47 (m, 3H), 3.20 (s, 3H), 2.15-2.07 (m, 3H),1.93-1.88 (m, 2H), 1.36-1.29 (m, 4H), 1.20 (t, J=7.2 Hz, 3H). MS: m/z475.3 (M+H⁺).

Example 91: Preparation of(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-yl)-dimethyl-amine

The 1^(st) two steps are similar to(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-ethoxycarbonylmethyl-amino]-aceticacid ethyl ester.

To a mixture of1-{2-Cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ylamine(62 mg, 0.112 mmol) in MeOH (5 mL), was added HCHO (3 mL) and HOAc (onedrop). The resulting mixture was stirred for 1 hour at room temperature.Then Na BH(OAc)₃ (119 mg, 0.560 mmol) and NaBCNH₃ (35 mg, 0.560 mmol)were added. The resulting mixture was stirred at room temperatureovernight. The solvent was removed under reduced pressure and theresidue was purified by Prep-HPLC and lyophilized with 2N HCl to afford(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-yl)-dimethyl-amine(3.7 mg, yield: 7%) as a white solid. ¹H NMR (300 HMz, CD₃OD): δ=7.67(d, J=9.0 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.24-7.19 (m, 2H), 7.00-6.92(m, 3H), 5.03-4.98 (m, 2H), 4.15-4.12 (m, 1H), 3.93-3.89 (m, 1H), 3.86(s, 3H), 3.77-3.73 (m, 2H), 3.56-3.48 (m, 4H), 3.20 (s, 3H), 3.01 (s,3H), 2.68-2.64 (m, 1H), 2.44-2.37 (m, 1H), 2.18-2.07 (m, 3H), 1.92-1.87(m, 2H), 1.37-1.31 (m, 4H). MS: m/z 472.3 (M+H⁺).

Example 92: Preparation of(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-ethoxycarbonylmethyl-amino]-aceticacid ethyl ester

To a mixture of6-bromo-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(1.12 g, 2.557 mmol), piperidin-4-yl-carbamic acid tert-butyl ester(1.02 g, 5.114 mmol) and Cs₂CO₃ (1.67 g, 5.114 mmol) in anhydroustoluene (100 mL), was added BINAP (318 mg, 0.511 mmol) and Pd(OAc)₂ (57mg, 0.256 mmol). The mixture was refluxed under N₂ at 110° C. overnight.The mixture was concentrated under reduced pressure. The residue waspartitioned between water (100 mL) and EtOAc (100 mL). The aqueous phasewas extracted with EtOAc (100 mL×2) and the extracts were dried overNa₂SO₄. The solution was concentrated and the residue was purifiedsilica gel column chromatography (PE/EA=30/1) to give(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-carbamicacid tert-butyl ester (3.3 g, yield: 27%) as a yellow solid. MS: m/z558.3 (M+H⁺).

To a solution of(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-carbamicacid tert-butyl ester (380 mg, 0.681 mmol) in dioxane (2 mL) was addedHCl in dioxane (4M, 0.68 mL). The reaction mixture was stirred at roomtemperature overnight. The mixture was concentrated under reducedpressure and the solid was dried in vacuum to give1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ylamine(380 mg, yield: 100%) as a yellow solid. MS: m/z 458.3 (M+H⁺).

To a mixture of1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ylamine(20 mg, 0.044 mmol) in DMF (2 mL), was added bromo-acetic acid ethylester (29 mg, 0.176 mmol) and K₂CO₃ (24 mg, 0.176 mmol). The resultingmixture was stirred at 100° C. overnight. The resulting mixture wasstirred at room temperature overnight. The mixture was purified byPrep-HPLC and lyophilized to afford(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-ethoxycarbonylmethyl-amino]-aceticacid ethyl ester (3.6 mg, yield: 13%) as a white solid. ¹H NMR (300 HMz,CD₃OD): δ=7.81 (dd, J=9.3, 2.1 Hz, 1H), 7.66 (d, J=9.3 Hz, 1H),7.39-7.37 (m, 1H), 7.24-7.19 (m, 2H), 7.00-6.92 (m, 2H), 4.99-4.97 (m,2H), 4.38-4.31 (m, 6H), 4.05-4.00 (m, 2H), 3.86 (s, 3H), 3.64-3.37 (m,6H), 3.02-2.95 (m, 2H), 2.23-1.92 (m, 9H), 1.39-1.30 (m, 10H). MS: m/z630.3 (M+H⁺).

Example 93:[(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-methyl-amino]-aceticacid ethyl ester

The title compound was prepared as described for(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-ethoxycarbonylmethyl-amino]-aceticacid ethyl ester. ¹H NMR (300 HMz, CD₃OD): δ=7.98-7.95 (m, 1H),7.75-7.72 (m, 2H), 7.24-7.19 (m, 2H), 6.99-6.92 (m, 2H), 5.00-4.93 (m,2H), 4.36 (q, J=7.2 Hz, 2H), 4.04-4.00 (m, 2H), 3.87 (s, 3H), 3.77-3.50(m, 5H), 3.27-3.23 (m, 2H), 3.02 (s, 3H), 2.34-2.13 (m, 9H), 1.39-1.31(m, 8H). MS: m/z 558.3 (M+H⁺).

Example 94: Preparation of2-{2-Dimethylamino-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylamino}-ethanol

A mixture of 2-amino-5-nitrobenzoic acid (20 g, 109.8 mmol) and urea (33g, 549.1 mmol) was heated at 200° C. for 2 hours. The resulting mixturewas washed with water, and the resulting solid was filtered and dried togive 6-nitroquinazoline-2,4(1H,3H)-dione (26 g, quantitative) as ayellow solid.

To a solution of 6-nitroquinazoline-2,4(1H,3H)-dione (34 g, 164.14 mmol)in POCl₃ (150 mL) was added dimethyl-phenyl-amine (60 g, 492.42 mmol).The mixture was stirred at 110° C. for 5 hours. The mixture wasconcentrated in vacuum and the remaining residue was neutralized by aq.NaHCO₃. The aqueous phase was extracted with EtOAc (80 mL×3). Theorganic phase was concentrated to dryness and the residue was purifiedby silica gel column chromatography (DCM:PE=2:1) to give2,4-dichloro-6-nitroquinazoline (5 g, yield: 13%) as a yellow solid.

To a solution of 2,4-dichloro-6-nitroquinazoline (3 g, 12.29 mmol) inEtOAc (50 mL) was added 4-(2-methoxyphenyl)piperidine (2.4 g, 12.29mmol) and DIEA (3.2 g, 24.59 mmol). The mixture was stirred at r.t.overnight. The reactant was diluted with PE and the mixture was stirredfor 15 min. The resulting solid was filtered to give2-chloro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline (4.5g, yield: 92%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ=8.83 (d,J=2.0 Hz, 1H), 8.50 (d, J=9.2, 2.4 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H),7.28-7.17 (m, 2H), 6.99 (d, J=7.6 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 4.67(d, J=13.2 Hz, 2H), 3.82 (s, 3H), 3.53 (t, J=12.0 Hz, 2H), 3.40-3.34 (m,1H), 1.94-1.83 (m, 4H).

To a solution of2-chloro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline (500mg, 1.25 mmol) in i-PrOH (5 mL) was added dimethyl-amine HCl salt (511mg, 6.27 mmol) and TEA (1 g, 10 mmol). The mixture was stirred at 80° C.for 3 hours. The mixture was concentrated to dryness in vacuum anddiluted with water (10 mL). The aqueous phase was extracted with CHCl₃(20 mL×3). The organic phase was concentrated to afford4-(4-(2-methoxyphenyl)piperidin-1-yl)-N,N-dimethyl-6-nitroquinazolin-2-amine(500 mg, yield: 98%) as a yellow solid.

To a solution of4-(4-(2-methoxyphenyl)piperidin-1-yl)-N,N-dimethyl-6-nitroquinazolin-2-amine(1 g, 2.45 mmol) in MeOH (20 mL) was added 10% Pd/C (200 mg). Thesuspension was was stirred at rt under H₂ atmosphere overnight. Thesuspension was filtered and the organic phase was concentrated in vacuumto give4-(4-(2-methoxyphenyl)piperidin-1-yl)-N,N-dimethylquinazoline-2,6-diamine(900 mg, yield: 97%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6):δ=7.76 (d, J=8.8 Hz, 1H), 7.24-7.18 (m, 2H), 7.13 (dd, J=8.8, 2.0 Hz,1H), 7.05 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.92 (t, J=7.6 Hz,1H), 5.55 (brs, 2H), 4.67 (d, J=12.8 Hz, 2H), 3.80 (s, 3H), 3.42-3.32(m, 3H), 3.23 (s, 6H), 1.94-1.78 (m, 4H).

To a solution of4-(4-(2-methoxyphenyl)piperidin-1-yl)-N,N-dimethylquinazoline-2,6-diamine(300 mg, 0.79 mmol) in DMF (5 mL) was added 2-bromo-ethanol (119 mg,0.95 mmol) and K₂CO₃ (329 mg, 2.38 mmol). And the mixture was stirred at80° C. overnight. The reactant was diluted with water (10 mL) and themixture was extracted with EtOAc (15 mL×3). The organic phase was driedover Na₂SO₄ and concentrated to give2-((2-(dimethylamino)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol (300 mg, crude) as a yellow oil.

To a solution of2-((2-(dimethylamino)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(150 mg, 0.36 mmol) in MeOH (5 mL) was added paraformaldehyde (108 mg,3.6 mmol) and NaCNBH₃ (113 mg, 1.8 mmol). And the mixture was stirred atr.t. overnight. The resulting mixture was concentrated in vacuum and theresidue was purified by Prep-HPLC to give2-{2-Dimethylamino-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylamino}-ethanol(11 mg, yield: 7%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆):δ=7.32-7.20 (m, 4H), 7.00-6.93 (m, 2H), 6.77 (s, 1H), 4.59 (t, J=6.8 Hz,1H), 4.28-4.23 (m, 2H), 3.81 (s, 3H), 3.58-3.32 (m, 5H), 3.13-3.07 (m,8H), 2.95 (s, 3H), 1.88-1.85 (m, 4H). LC-MS: 436.2 (M+H⁺).

Example 95: Preparation of4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2,N6-trimethyl-N6-propylquinazoline-2,6-diamine

and Example 96: Preparation of4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2-dimethyl-N6,N6-dipropylquinazoline-2,6-diamine

To a solution of4-(4-(2-methoxyphenyl)piperidin-1-yl)-N,N-dimethylquinazoline-2,6-diamine(300 mg, 0.79 mmol) in DMF (5 mL) was added 1-bromo-propane (117 mg,0.95 mmol) and K₂CO₃ (329 mg, 2.38 mmol). And the mixture was stirred at80° C. overnight. The reactant was diluted with water (10 mL) and themixture was extracted with EtOAc (15 mL×3). The organic phase was driedover Na₂SO₄ and concentrated to dryness. The residue was purified byprep-HPLC to afford byproduct4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2-dimethyl-N6,N6-dipropylquinazoline-2,6-diamine(20 mg) as a yellow solid and intermediate4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2-dimethyl-N6-propylquinazoline-2,6-diamine(50 mg, yield: 15%) as a yellow oil.

Byproduct: ¹H NMR (400 MHz, CD₃OD): δ=7.80-7.91 (m, 3H), 7.26-7.21 (m,2H), 7.00-6.92 (m, 2H), 4.84 (d, J=13.2 Hz, 2H), 3.88 (s, 3H), 3.63-3.39(m, 7H), 3.39 (s, 6H), 2.12-1.97 (m, 4H), 1.71-1.56 (m, 4H), 0.99 (t,J=6.8 Hz, 6H). LC-MS: 462.3 (M+H⁺).

To a solution of4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2-dimethyl-N6-propylquinazoline-2,6-diamine(150 mg, 0.36 mmol) in MeOH (5 mL) was added paraformaldehyde (128 mg,3.6 mmol), NaCNBH₃ (113 mg, 1.8 mmol). The mixture was stirred at r.t.overnight. The resulting mixture was concentrated to dryness in vacuumand the residue was purified by prep-HPLC to afford4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2,N6-trimethyl-N6-propylquinazoline-2,6-diamine(15 mg, yield: 10%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=7.46(d, J=9.2 Hz, 1H), 7.30-7.17 (m, 3H), 6.96-6.87 (m, 3H), 4.34 (d, J=12.8Hz, 2H), 3.85 (s, 3H), 3.34-3.24 (m, 3H), 3.21 (s, 6H), 3.13-3.06 (m,2H), 2.96 (s, 3H), 1.96-1.91 (m, 4H), 1.65-1.60 (m, 2H), 0.95 (t, J=7.2Hz, 3H). LC-MS: 434.3 (M+H⁺).

Example 97: Preparation ofN2-Cyclobutyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-N6-methyl-N6-propyl-quinazoline-2,6-diamine

The title compound was prepared as described for4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2,N6-trimethyl-N6-propylquinazoline-2,6-diamine.¹H NMR (300 MHz, DMSO-d₆): δ=8.32-8.30 (m, 1H), 7.45-6.89 (m, 5H), 6.82(s, 1H), 4.72-4.62 (m, 2H), 4.53-4.43 (m, 1H), 3.81 (s, 3H), 3.46-3.26(m, 5H), 2.94 (s, 3H), 2.37-2.26 (m, 2H), 2.10-1.48 (m, 10H), 1.65-1.60(m, 2H), 0.92 (t, J=7.2 Hz, 3H). LC-MS: 460.3 (M+H⁺).

Example 98: Preparation of2-((2-(cyclobutylamino)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol

The title compound was prepared as described for4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2,N6-trimethyl-N6-propylquinazoline-2,6-diamine.¹H NMR (400 MHz, DMSO-d6): δ=7.28-7.20 (m, 4H), 7.01-6.93 (m, 2H), 6.78(s, 1H), 6.63-6.61 (m, 1H), 4.68 (s, 1H), 4.46-4.43 (m, 1H), 4.23-4.18(m, 2H), 3.83 (s, 3H), 3.59-3.50 (m, 2H), 3.23-3.18 (m, 1H), 3.05-3.00(m, 2H), 2.96 (s, 3H), 2.54-2.23 (m, 2H), 2.00-1.87 (m, 6H), 1.65-1.62(m, 2H). LC-MS: 462.3 (M+H⁺).

Example 99: Preparation of2-({2-cyclopropyl-4-[6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

To a solution of 2,6-diaza-spiro[3.3]heptane-2-carboxylic acidtert-butyl ester (1 g, 5.1 mmol) in toluene (20 mL) was added2-methoxy-phenylamine (807 mg, 6.56 mmol), Pd₂(dba)₃ (200 mg), x-phos(300 mg) and Cs₂CO₃ (3.29 g, 10.2 mmol). It was then refluxed overnight.Resultant was purified by flash column (EA in PE: 0 to 50%) to afford6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acidtert-butyl ester (1.2 g, yield: 78%) as a white solid.

To as solution of6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acidtert-butyl ester (200 mg, 0.66 mmol) in DCM (5 mL) was added TFA (5 mL),it was then stirred overnight. Resultant was concentrated in vacuum toafford crude 2-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]heptanes withoutfurther purification.

The last step is similar to example2-[(2-cyclopropyl-4-{2-[(2-methoxy-phenyl)-methyl-amino]-cyclopentylamino}-quinazolin-6-yl)-methyl-amino]-ethanol.¹HNMR (400 MHz, CD₃OD): δ=7.55 (d, J=9.3 Hz, 1H), 7.38 (d, J=8.8, 2.4Hz, 1H), 6.94 (s, 1H), 6.85 (d, J=5.4 Hz, 3H), 6.55-6.53 (m, 1H), 4.61(brs, 4H), 4.04 (brs, 4H), 3.81-3.75 (m, 5H), 3.54-3.51 (m, 2H), 3.06(s, 3H), 2.04 (m, 1H), 1.13 (s, 2H), 0.94-0.92 (m, 2H). MS: m/z 446.2(M+H⁺).

Example 100: Preparation of{2-cyclopropyl-4-[6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹HNMR (400 MHz, CDCl₃): δ=7.64 (d, J=9.2 Hz, 1H), 7.27-7.24 (m, 1H),6.91-6.78 (m, 4H), 6.49 (d, J=7.6 Hz, 1H), 4.60 (s, 4H), 4.11 (s, 4H),3.81 (s, 3H), 3.32 (t, J=5.4 Hz, 2H), 2.98 (s, 3H), 2.13-2.09 (m, 1H),1.65-1.60 (m, 2H), 1.12-1.10 (m, 2H), 0.96-0.89 (m, 5H). MS: m/z 444.2(M+H⁺).

Example 101: Preparation of{2-cyclopropyl-4-[6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹HNMR (400 MHz, CD₃OD): δ=7.57 (d, J=9.2 Hz, 1H), 7.37 (dd, J=9.2, 2.4Hz, 1H), 6.88-6.81 (m, 4H), 6.51 (dd, J=7.6, 2.4 Hz, 1H), 4.60 (s, 4H),4.02 (s, 4H), 3.79 (s, 3H), 3.68 (t, J=4.8 Hz, 4H), 3.55 (t, J=7.2 Hz,2H), 3.02 (s, 3H), 2.56-2.50 (m, 6H), 2.05-2.03 (m, 1H), 1.15-1.12 (m,2H), 0.96-0.93 (m, 2H). MS: m/z 515.3 (M+H⁺)

Example 102: Preparation of1-[2-cyclopropyl-6-(methyl-propyl-amino)-quinazolin-4-yl]-4-(2-methoxy-phenyl)-piperidin-2-one

To a mixture of 1-bromo-2-methoxy-benzene (5.1 g, 27.2 mmol),2-bethoxypyridne-4-boronic acid (5.0 g, 32.7 mmol), H₂O (30 mL) andK₂CO₃ (7.5 g, 54 mmol) in dioxane (90 mL) was added Pd(dppf)Cl₂ (222 mg,0.27 mmol). The mixture was stirred at 100° C. under N₂ for overnight,cooled to room temperature and evaporated under reduced pressure todryness. The residue was diluted with EA (100 mL×2) and washed withwater, dried over anhydrous Na₂SO₄, filtered. The filtrate wasevaporated in vacuum to residue, which was purified by silica gelchromatography (from PE to PE/EA=10/1) to give (5.3 g, yield: 91%) of2-methoxy-4-(2-methoxy-phenyl)-pyridine as yellow oil. MS: m/z 216.2(M+H⁺).

To a stirred solution of 2-methoxy-4-(2-methoxy-phenyl)-pyridine (2.2 g,10.2 mmol) in dioxane (40 mL) was added HCl (14 mL). The mixture wasthen heated to reflux overnight. The reaction was cooled to roomtemperature and was concentrated. The residue was washed with water andDCM. and the solid was evaporated in vacuum to dryness to afford (1.4 gyield: 67%) of 4-(2-methoxy-phenyl)-pyridin-2-ol as a white solid. MS:m/z 202.2 (M+H⁺).

A suspension of 4-(2-methoxy-phenyl)-pyridin-2-ol (1.0 g, 5.0 mmol),CH₃COOH (5 ml) and Pd/C (600 mg) in ethanol (20 mL) was degassed with H₂for 3 times, and the resulting mixture was stirred under H₂ (4 MPa) for16 hours. TLC showed the reaction was completed. Then the reaction wasfiltered, he residue was washed with ethanol (10 ml). and the solid wasevaporated in vacuum to dryness to afford (800 mg, yield: 52%) of4-(2-methoxy-phenyl)-piperidin-2-one as a white solid.

To a solution of 6-bromo-2-cyclopropyl-quinazolin-4-ol (2 g, 7.6 mmol)in DMSO (20 mL) were added methyl-propyl-amine (693 mg, 11.4 mmol), CuI(500 mg), proline (500 mg) and K₂CO₃ (6.4 g, 16.7 mmol). The mixture wasstirred at 90° C. overnight under the protection of N₂. The resultantwas purified by pre-HPLC to give (1.4 g, yield: 75%) of2-cyclopropyl-6-(methyl-propyl-amino)-quinazolin-4-ol.

To a stirred solution of2-cyclopropyl-6-(methyl-propyl-amino)-quinazolin-4-ol (100 mg, 0.39mmol) in POCl₃(10 mL). The mixture was then heated to reflux 2 h. Thereaction was cooled to room temperature and was concentrated. and addedinto ice water (50 mL) dropwise. The aqueous mixture was neutralizedwith sat.NaHCO₃ to pH=8 and extracted with EA (20 mL×2). The combinedorganic layers were washed with brine (10 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate was evaporated in vacuum to residue,which was purified by silica gel chromatography (from PE to PE/EA=5/1)to give (100 mg, yield: 93%) of(4-Chloro-2-cyclopropyl-quinazolin-6-yl)-methyl-propyl-amine as yellowsolid. MS: m/z 276.1 (M+H⁺).

To a suspension of(4-chloro-2-cyclopropyl-quinazolin-6-yl)-methyl-propyl-amine (100 mg,0.36 mmol) in anhydrous THF (20 mL) was added4-(2-methoxy-phenyl)-piperidin-2-one (88 mg, 0.43 mmol), xant-phos (6mg, 0.01 mmol), Cs₂CO₃ (236 mg, 0.72 mmol) and Pd₂(dba)₃ (5.0 mg, 0.024mmol). The mixture was refluxed under N₂ for o/n. The mixture wasconcentrated under reduced pressure, the residue was partitioned betweenwater (60 mL) and EA (30 mL), extracted with EA (15 mL×2), dried overNa₂SO₄, concentrated, purified Pre-TLC (PE/EA=5/1) to give 100 mg of1-[2-cyclopropyl-6-(methyl-propyl-amino)-quinazolin-4-yl]-4-(2-methoxy-phenyl)-piperidin-2-oneas a pale yellowsolid. ¹H NMR (400 MHz, CD₃OD): δ=7.67 (d, J=9.6 Hz,1H), 7.52 (dd, J=9.2, 2.4 Hz, 1H), 7.19-7.14 (m, 2H), 6.92-6.85 (m, 2H),6.50 (d, J=2.4 Hz, 1H), 3.66-3.62 (m, 2H), 3.34 (t, J=7.6 Hz, 2H), 2.96(s, 3H), 2.80-2.61 (m, 2H), 2.25-2.13 (m, 3H), 1.59-1.53 (m, 2H),1.05-0.96 (m, 4H), 0.94-0.92 (m, 3H). MS: m/z 445.2 (M+H⁺).

Example 103: Preparation of2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

To a mixture of 2-amino-6-chloro-benzoic acid (2.0 g, 11.6 mmol) andK₂CO₃ (2.4 g, 17.4 mmol) in DMF (30 mL) was added dropwise Iodomethane(0.94 mL, 15.1 mmol) and the reaction mixture was stirred at rt for 18h. The reaction mixture was quenched with water (200 mL), the aqueouslayer was extracted with Et₂O (3×100 mL), dried over Na₂SO₄. The mixturewas filtered and the solvent removed by evaporation under reducedpressure to give an orange residue, which was purified by column(PE/EA=50/1-40/1-20/1) to give 2-amino-6-chloro-benzoic acid methylester (1.7 g, yield: 82%) as an orange oil. ¹H NMR (400 MHz, CDCl₃):δ=7.07 (t, J=8.0 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.57 (d, J=8.8 Hz,1H), 4.87 (brs, 2H), 3.92 (s, 3H).

To a solution of 2-amino-6-chloro-benzoic acid methyl ester (1.7 g, 9.1mmol) in DMF (10 mL) at −10° C., NBS (1.6 g, 9.1 mmol) in DMF (6 mL) wasadded dropwise over 10 min. After the addition was complete, thereaction mixture was stirred at −10° C. for 1 h. The reaction wasquenched with aqueous sodium bisulfate (50 mL), the aqueous layer wasextracted with EA (2×100 mL), the organic layers were washed with brine(100 mL×2), dried over Na₂SO₄, concentrated and purified by column(PE/EA=50/1-40/1) to afford 6-amino-3-bromo-2-chloro-benzoic acid methylester (2 g, yield: 82%) as an orange solid. 1H NMR (400 MHz, CDCl₃):δ=7.39 (d, J=8.8 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.68 (brs, 2H), 3.94(s, 3H).

The mixture of 6-amino-3-bromo-2-chloro-benzoic acid methyl ester (1.0g, 3.8 mmol) and cyclopropanecarbonitrile (1.3 g, 18.8 mmol) inHCl/dioxane (10 mL) was stirred at reflux overnight. The solid wasfiltered, dried to give 6-bromo-5-chloro-2-cyclopropyl-quinazolin-4-ol(1.0 g, yield: 91%) as white solid. ¹H NMR (400 HMz, DMSO-d₆): δ=8.04(d, J=9.2 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 2.05-2.03 (m, 1H), 1.19-1.11(m, 4H).

A mixture of 6-bromo-5-chloro-2-cyclopropyl-quinazolin-4-ol (200 mg,0.67 mmol), 4-(2-methoxy-phenyl)-piperidine hydrochloride (167 mg, 0.74mmol), DBU (509 mg, 3.35 mmol), and BOP (444 mg, 1.0 mmol) in ACN (20mL) was stirred at 25° C. for 16 h. The solid appeared, then filtered,the solid was washed with ACN, dried to give (153 mg, yield: 48%)6-bromo-5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolineas a white solid.

To a solution of6-bromo-5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(153 mg, 0.32 mmol) in anhydrous toluene (10 mL) was added BINAP (60 mg,0.096 mmol), Pd(OAc)₂ (11 mg, 0.048 mmol) and Cs₂CO₃ (209 mg, 0.64mmol), purged with N₂ for 15 min, 2-(tert-butyl-dimethyl-silanyloxy)-ethylamine (114 mg, 0.64 mmol) was added. The mixture was refluxed underN₂ for 16 h. The mixture was cooled to rt, filtered, the filtraction wasconcentrated to give[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-{5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-amineas a crude product, which was used to next step without furtherpurification.

To a solution of[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-{5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-amine(crude, 0.32 mmol) in MeOH (20 mL) was added HCHO (0.5 mL, 40% in H₂O,6.4 mmol), NaBH(ACO)₃ (678 mg, 3.2 mmol) and NaBH₃CN (202 mg, 3.2 mmol).Then the reaction mixture was stirred at rt overnight. NaHCO₃ solutionwas added, then extracted with EA (50 mL×3), the organic layer waswashed with brine, dried over Na₂SO₄, concentrated, the residue was usedto next step without further purification

To a solution of[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-{5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amine(crude, 0.32 mmol) in MeOH (30 mL) was added con. HCl (0.3 mL), thereaction mixture was stirred at rt overnight. NH₃H₂O was added to adjustpH to 7-8, the mixture was concentrated, purified by prep-TLC(DCM/MeOH=20/1), further purified by prep-HPLC to give (23.3 mg, yield:61%)2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanolas a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=7.71-7.56 (m, 2H),7.31-7.15 (m, 2H), 7.02-6.99 (m, 1H), 6.90-6.84 (m, 1H), 4.30 (d, J=10.4Hz, 1H), 4.08 (d, J=10.0 Hz, 1H), 3.84 (d, J=8.0 Hz, 3H), 3.68-3.67 (m,2H), 3.48-3.41 (m, 1H), 3.32-3.11 (m, 3H), 2.88-2.72 (m, 5H), 2.18-1.96(m, 3H), 1.77-1.59 (m, 1H), 1.18-1.15 (m, 2H), 1.03-0.99 (m, 2H). MS:m/z 467 (M+H⁺)

Example 104: Preparation of{7-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.75 (s, 1H), 7.19-7.15 (m, 3H), 6.90-6.87(m, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.27 (d, J=13.2 Hz, 2H), 3.79 (s, 3H),3.25-3.11 (m, 3H), 2.96-2.92 (m, 2H), 2.75 (s, 3H), 2.11-2.05 (m, 1H),1.89-1.83 (m, 4H), 1.56-1.55 (m, 2H), 1.09-1.08 (m, 2H), 0.92-0.89 (m,2H), 0.85 (t, J=7.6 Hz, 3H). MS: m/z 465.2 (M+H⁺)

Example 105: Preparation of{2-cyclopropyl-7-fluoro-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.39 (d, J=13.2 Hz, 1H), 7.24-7.21 (m, 2H),7.13 (d, J=9.6 Hz, 1H), 6.97 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H),4.32 (d, J=12.8 Hz, 2H), 3.86 (s, 3H), 3.30-3.25 (m, 1H), 3.18-3.12 (m,4H), 2.89 (s, 3H), 2.18-2.15 (m, 1H), 1.98-1.87 (m, 4H), 1.64-1.59 (m,3H), 1.16-1.14 (m, 2H), 0.99-0.97 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). MS:m/z 449.2 (M+H⁺)

Example 106: Preparation of{4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-7-fluoro-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.39 (d, J=14.0 Hz, 1H), 7.22-7.11 (m, 3H),6.90 (t, J=7.4 Hz, 1H), 6.61 (d, J=7.6 Hz, 1H), 4.31 (d, J=12.8 Hz, 2H),3.94 (t, J=7.2 Hz, 4H), 3.17-2.98 (m, 5H), 2.89 (s, 3H), 2.33-2.30 (m,2H), 2.18-2.15 (m, 1H), 2.03-1.89 (m, 4H), 1.64-1.59 (m, 3H), 1.16-1.14(m, 2H), 0.99-0.97 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). MS: m/z 474.3 (M+H⁺)

Example 107: Preparation of2-({7-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described in example2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.32 (brs, 1H), 7.46 (s, 1H), 7.25-7.17 (m,2H), 6.99-6.97 (m, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.70 (brs, 2H), 3.86 (s,3H), 3.83-3.80 (m, 2H), 3.41-3.36 (m, 3H), 3.29-3.27 (m, 2H), 2.88 (s,3H), 2.75 (brs, 1H), 2.10-2.07 (m, 2H), 1.91-1.83 (m, 2H), 1.25-1.20 (m,5H). MS: m/z 467.2 (M+H⁺)

Example 108: Preparation of2-({2-cyclopropyl-4-[4-(4-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.70 (d, J=8.8 Hz, 1H), 7.36-7.34 (m, 1H),7.15 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 6.67-6.60 (m, 2H), 4.33 (d, J=13.2Hz, 2H), 3.88-3.84 (m, 5H), 3.56-3.53 (m, 2H), 3.21-3.09 (m, 3H), 3.04(s, 3H), 2.17 (brs, 1H), 21.94-1.83 (m, 4H), 1.17-1.14 (m, 2H),0.97-0.94 (m, 2H). MS: m/z 451.2 (M+H⁺)

Example 109: Preparation of2-({2-cyclopropyl-4-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.76 (brs, 1H), 7.38-7.35 (m, 1H), 6.96-6.81(m, 4H), 4.35 (d, J=8.4 Hz, 2H), 3.87 (t, J=5.6 Hz, 2H), 3.83 (s, 3H),3.55 (t, J=5.2 Hz, 2H), 3.28-3.13 (m, 3H), 3.05 (s, 3H), 2.22-2.21 (m,1H), 1.98-1.82 (m, 5H), 1.16-0.97 (m, 4H). MS: m/z 451.3 (M+H⁺)

Example 110: Preparation of2-({2-cyclopropyl-7-fluoro-4-[4-(4-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.98 (d, J=12.8 Hz, 1H), 7.25-7.23 (m, 1H),7.11-7.07 (m, 1H), 6.67-6.61 (m, 2H), 4.79-4.75 (m, 2H), 3.88-3.84 (m,5H), 3.43-3.32 (m, 5H), 3.00 (s, 3H), 2.72-2.70 (m, 1H), 2.08-2.04 (m,2H), 1.83-1.80 (m, 2H), 1.38-1.18 (m, 5H). MS: m/z 469.3 (M+H⁺)

Example 111: Preparation of2-({2-cyclopropyl-7-fluoro-4-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 HMz, CDCl₃): δ=7.46 (d, J=12.6 Hz, 1H), 7.30 (s, 1H),6.93-6.83 (m, 3H), 4.32 (d, J=11.1 Hz, 2H), 3.87-3.85 (m, 5H), 3.34-3.13(m, 5H), 2.95 (s, 3H), 2.21-2.19 (m, 1H), 1.89-1.77 (m, 4H), 1.19-1.16(m, 2H), 1.03-1.00 (m, 2H). MS: m/z 469.3 (M+H⁺)

Example 112: Preparation of2-({7-chloro-2-cyclopropyl-4-[4-(4-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.85 (s, 1H), 7.46 (s, 1H), 7.15-7.11 (t,J=7.8 Hz, 1H), 6.67-6.61 (m, 2H), 4.34 (d, J=12.8 Hz, 2H), 3.84 (s, 3H),3.79-3.76 (m, 2H), 3.25-3.16 (m, 5H), 2.83 (s, 3H), 2.51-2.49 (m, 1H),2.17 (brs, 1H), 1.96-1.82 (m, 4H), 1.18-1.16 (m, 2H), 1.02-0.99 (m, 2H).MS: m/z 485.2 (M+H⁺)

Example 113: Preparation of2-({7-chloro-2-cyclopropyl-4-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.77 (s, 1H), 7.39 (s, 1H), 6.88-6.82 (m,2H), 6.75-6.73 (m, 1H), 4.25 (d, J=13.2 Hz, 2H), 3.76 (s, 3H), 3.73-3.70(m, 2H), 3.19-3.08 (m, 5H), 2.77 (s, 3H), 2.60 (brs, 1H), 2.12-2.06 (m,1H), 1.91-1.88 (m, 2H), 1.77-1.73 (m, 2H), 1.10-1.08 (m, 2H), 0.94-0.91(m, 2H). MS: m/z 485.2 (M+H⁺)

Example 114: Preparation of2-({2-cyclopropyl-4-[4-(4-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.63 (s, 1H), 7.42 (s, 1H), 7.16-7.13 (m,1H), 6.67-6.60 (m, 2H), 4.35 (d, J=13.2 Hz, 2H), 3.84 (s, 3H), 3.77-3.74(m, 2H), 3.21-3.15 (m, 5H), 2.73 (s, 3H), 2.47 (s, 3H), 2.18-2.15 (m,1H), 1.95-1.83 (m, 4H), 1.17-1.15 (m, 2H), 0.99-0.97 (m, 2H). MS: m/z429.3 (M+H⁺)

Example 115: Preparation of2-({2-cyclopropyl-4-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described in example2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.62 (s, 1H), 7.42 (s, 1H), 6.96-6.93 (m,1H), 6.89-6.86 (m, 1H), 6.82-6.79 (m, 1H), 4.33 (d, J=13.2 Hz, 2H), 3.83(s, 3H), 3.78-3.75 (m, 2H), 3.25-3.13 (m, 5H), 2.73 (s, 3H), 2.47 (s,3H), 2.19-2.16 (m, 1H), 1.97-1.81 (m, 4H), 1.17-1.14 (m, 2H), 0.99-0.96(m, 2H). MS: m/z 465.3 (M+H⁺)

Example 116: Preparation of2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.71 (s, 1H), 7.43 (s, 1H), 7.28-7.09 (m,4H), 4.43 (d, J=13.2 Hz, 2H), 3.78-3.75 (m, 2H), 3.52-3.51 (m, 1H),3.26-3.15 (m, 4H), 2.74 (s, 3H), 2.70 (s, 6H), 2.47 (s, 3H), 2.27 (brs,1H), 1.93-1.91 (m, 4H), 1.19-1.17 (m, 2H), 1.03-1.01 (m, 2H). MS: m/z460.3 (M+H⁺)

Example 117: Preparation of2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.62 (s, 1H), 7.43 (s, 1H), 7.24-7.21 (m,2H), 6.99-6.95 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.35 (d, J=13.2 Hz, 2H),3.86 (s, 3H), 3.77-3.74 (m, 2H), 3.31-3.26 (m, 1H), 3.21-3.15 (m, 4H),2.73 (s, 3H), 2.47 (s, 3H), 2.37-2.36 (m, 1H), 2.18-2.15 (m, 1H),1.98-1.87 (m, 4H), 1.18-1.15 (m, 2H), 0.99-0.96 (m, 2H). MS: m/z 447.3(M+H⁺)

Example 118: Preparation of2-({7-chloro-2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.86 (s, 1H), 7.49 (s, 1H), 7.28 (m, 1H),7.21-7.17 (m, 2H), 7.13-7.11 (m, 1H), 4.36 (d, J=13.2 Hz, 2H), 3.80-3.77(m, 2H), 3.53-3.49 (m, 1H), 3.26-3.20 (m, 4H), 2.84 (s, 3H), 2.70 (s,6H), 2.20-2.16 (m, 1H), 1.92-1.88 (m, 4H), 1.18-1.16 (m, 2H), 1.02-0.99(m, 2H). MS: m/z 480.2 (M+H⁺)

Example 119: Preparation of2-({4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-7-chloro-2-cyclopropyl-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.84 (s, 1H), 7.49 (s, 1H), 7.26-7.14 (m,2H), 6.91-6.89 (m, 1H), 6.61 (d, J=7.6 Hz, 1H), 4.34 (d, J=13.2 Hz, 2H),3.96-3.92 (m, 4H), 3.79-3.77 (m, 2H), 3.24-3.12 (m, 4H), 3.04-3.02 (m,1H), 2.84 (s, 3H), 2.71-2.69 (m, 1H), 2.33-2.30 (m, 2H), 2.17 (brs, 1H),2.04-1.88 (m, 4H), 1.18-1.15 (m, 2H), 0.99-0.96 (m, 2H). MS: m/z 492.3(M+H⁺)

Example 120: Preparation of2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-7-fluoro-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.40 (d, J=13.6 Hz, 1H), 7.29-7.27 (m, 2H),7.21-7.17 (m, 2H), 7.12-7.09 (m, 1H), 4.33 (d, J=13.2 Hz, 2H), 3.84 (m,2H), 3.52-3.48 (m, 1H), 3.33 (m, 2H), 3.22-3.15 (m, 2H), 2.93 (s, 3H),2.70 (s, 6H), 2.17-2.15 (m, 1H), 1.98-1.91 (m, 4H), 1.18-1.15 (m, 2H),0.99-0.96 (m, 2H). MS: m/z 464.3 (M+H⁺)

Example 121: Preparation of2-({4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-7-methyl-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.63 (s, 1H), 7.42 (s, 1H), 7.22-7.14 (m,2H), 6.91-6.89 (m, 1H), 6.62 (d, J=7.6 Hz, 1H), 4.34 (d, J=13.6 Hz, 2H),3.96-3.93 (m, 4H), 3.77-3.75 (m, 2H), 3.18-3.09 (m, 5H), 2.74 (s, 3H),2.48 (s, 3H), 2.35-2.20 (m, 3H), 2.02-1.89 (m, 4H), 1.17-1.15 (m, 2H),0.99-0.97 (m, 2H). MS: m/z 472.3 (M+H⁺)

Example 122: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.60 (s, 1H), 7.32 (s, 1H), 7.26-7.20 (m,2H), 6.99-6.95 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.35 (d, J=13.2 Hz, 2H),3.86 (s, 3H), 3.29-3.12 (m, 3H), 2.89-2.86 (m, 2H), 2.72 (s, 3H), 2.44(s, 3H), 2.17-2.16 (m, 1H), 1.98-1.88 (m, 5H), 1.61-1.56 (q, J=7.2 Hz,2H), 1.18-1.15 (m, 2H), 0.98-0.93 (m, 5H). MS: m/z 445.3 (M+H⁺)

Example 123: Preparation of{2-cyclopropyl-4-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.61 (s, 1H), 7.31 (s, 1H), 6.97-6.94 (m,1H), 6.91-6.87 (m, 1H), 6.82-6.81 (m, 1H), 4.34 (d, J=13.2 Hz, 2H), 3.83(s, 3H), 3.29-3.22 (m, 1H), 3.17-3.11 (t, J=11.2 Hz, 2H), 2.90-2.86 (t,J=7.2 Hz, 2H), 2.72 (s, 3H), 2.44 (s, 3H), 2.21-2.16 (m, 1H), 1.97-1.82(m, 4H), 1.62-1.56 (m, 2H), 1.16-1.14 (m, 2H), 0.98-0.89 (m, 5H). MS:m/z 463.3 (M+H⁺)

Example 124: Preparation of2-({2-cyclopropyl-7-fluoro-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.40 (d, J=13.2 Hz, 1H), 7.30-7.20 (m, 3H),6.98-6.95 (m, 1H), 6.91-6.89 (m, 1H), 4.32 (d, J=12.8 Hz, 2H), 3.86 (s,3H), 3.83-3.82 (m, 2H), 3.33-3.28 (m, 3H), 3.20-3.14 (m, 2H), 2.92 (s,3H), 2.18 (brs, 1H), 1.99-1.87 (m, 4H), 1.18-1.14 (m, 2H), 1.00-0.97 (m,2H). MS: m/z 463.3 (M+H⁺)

Example 125: Preparation of2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol

The procedures of most steps are similar to2-({5-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanolexcept step 2 and 3, which are identical to the first two steps of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-5-yl}-methyl-propyl-amine.¹H NMR (300 HMz, CDCl3): δ=7.26-7.21 (m, 3H), 7.01-6.85 (m, 3H), 4.34(d, J=10.8 Hz, 2H), 3.89-3.85 (m, 5H), 3.56-3.54 (m, 2H), 3.32-3.09 (m,3H), 3.03 (s, 3H), 2.71 (s, 3H), 2.24-2.21 (m, 1H), 1.96-1.88 (m, 4H),1.19-1.17 (m, 2H), 1.01-0.97 (m, 2H). MS: m/z 447.2 (M+H⁺)

Example 126: Preparation of2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-5-methyl-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.63 (t, J=11.2 Hz, 1H), 7.52 (t, J=10.4 Hz,1H), 7.28-7.14 (m, 2H), 7.00-6.83 (m, 2H), 4.25 (d, J=12.8 Hz, 1H), 3.95(d, J=13.6 Hz, 1H), 3.83 (d, J=10.0 Hz, 3H), 3.71-3.68 (m, 2H),3.38-3.33 (m, 1H), 3.18-3.15 (m, 2H), 2.84-2.78 (m, 3H), 2.74 (s, 3H),2.60 (s, 1H), 2.18-2.16 (m, 1H), 2.02-1.99 (m, 2H), 1.71-1.53 (m, 5H),1.19-1.15 (m, 2H), 0.98-0.97 (m, 2H). MS: m/z 447.2 (M+H⁺)

Example 127: Preparation of2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-8-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.29 (brs, 1H), 7.37 (d, J=7.6 Hz, 1H),7.24-7.19 (m, 3H), 7.14 (d, J=7.6 Hz, 1H), 6.97-6.95 (m, 1H), 6.89 (d,J=7.6 Hz, 1H), 4.45 (d, J=13.2 Hz, 2H), 4.02-3.99 (m, 2H), 3.85 (s, 3H),3.46-3.43 (m, 2H), 3.30-3.15 (m, 3H), 2.97 (s, 3H), 2.25-2.21 (m, 1H),1.94-1.83 (m, 4H), 1.17-1.15 (m, 2H), 0.99-0.97 (m, 2H). MS: m/z 434.3(M+H⁺)

Example 128: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-8-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.36 (d, J=8.0 Hz, 1H), 7.25-7.18 (m, 3H),7.00-6.96 (m, 2H), 6.89 (d, J=8.4 Hz, 1H), 4.38 (d, J=12.8 Hz, 2H), 3.86(s, 3H), 3.50-3.46 (m, 2H), 3.29-3.14 (m, 3H), 2.98 (s, 3H), 2.27-2.24(m, 1H), 1.94-1.91 (m, 4H), 1.73-1.71 (m, 2H), 1.18-1.16 (m, 2H),0.98-0.95 (m, 2H), 0.90 (t, J=7.6 Hz, 3H). MS: m/z 431.3 (M+H⁺)

Example 129: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-8-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.37 (d, J=8.0 Hz, 1H), 7.24-7.17 (m, 3H),7.03-6.98 (m, 1H), 6.96-6.88 (m, 2H), 4.38 (d, J=12.8 Hz, 2H), 3.86 (s,3H), 3.70-3.63 (m, 6H), 3.17-3.10 (m, 3H), 3.01 (s, 3H), 2.81-2.77 (m,2H), 2.48 (brs, 4H), 2.25 (brs, 1H), 1.93-1.87 (m, 4H), 1.17-1.16 (m,2H), 0.97-0.94 (m, 2H). MS: m/z 502.3 (M+H⁺)

Example 130: Preparation of2-({8-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.46 (s, 1H), 7.24-7.20 (m, 2H), 6.98-6.88(m, 3H), 6.90-6.84 (m, 1H), 4.32 (d, J=13.2 Hz, 2H), 3.88-3.85 (m, 5H),3.55-3.52 (m, 2H), 3.34-3.14 (m, 3H), 3.04 (s, 3H), 2.28-2.32 (m, 1H),1.94-1.87 (m, 5H), 1.18- 1.16 (m, 2H), 0.99-0.97 (m, 2H). MS: m/z 467.3(M+H⁺)

Example 131: Preparation of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-5-yl}-methyl-propyl-amine

To a solution of 2-amino-6-bromo-benzoic acid (2 g, 9.3 mmol) inpyridine (20 mL) was added cyclopropanecarbonyl chloride (1.25 mL, 13.9mmol). The reaction mixture was stirred at 60° C. overnight. Cooled to0° C., and poured into ice-water (100 mL), the resulting suspension wasfiltered and dried to give5-bromo-2-cyclopropyl-benzo[d][1,3]oxazin-4-one (1.75 g, yield: 71%) aswhite solid. ¹H NMR (300 HMz, CDCl₃): δ=7.68 (d, J=7.8 Hz, 1H), 7.53 (t,J=8.1 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 1.95-1.90 (m, 1H), 1.31-1.27 (m,2H), 1.16-1.11 (m, 2H).

A suspension of 5-bromo-2-cyclopropyl-benzo[d][1,3]oxazin-4-one (1 g,3.79 mmol) in NH₃H₂O (50 mL, 28%) was heated at reflux overnight. Cooledto rt, filtered, the cake was washed with water, dried to give5-bromo-2-cyclopropyl-quinazolin-4-ol (450 mg, 45% yield) as whitesolid. ¹H NMR (300 HMz, CDCl₃): δ=7.64-7.62 (m, 1H), 7.56-7.53 (m, 1H),7.50-7.47 (m, 1H), 1.84-1.82 (m, 1H), 1.32-1.28 (m, 2H), 1.17-1.13 (m,2H).

To a suspension of 5-bromo-2-cyclopropyl-quinazolin-4-ol (100 mg, 0.38mmol), L-proline (22 mg, 0.19 mmol), CuI (22 mg, 0.11 mmol) and K₂CO₃(105 mg, 0.76 mmol) in DMSO (2 mL) was added methyl-propyl-amine (41 mg,0.57 mmol) after purged with N₂ for 5 min. Then the mixture was heatedto 90° C. and it was stirred at a sealed tube overnight. Cooled to rt,filtered, the filtration was purified by prep-HPLC to afford2-cyclopropyl-5-(methyl-propyl-amino)-quinazolin-4-ol (23 mg, yield:21%) as brown oil. MS: m/z 258.0 (M+H⁺)

To a suspension of 2-cyclopropyl-5-(methyl-propyl-amino)-quinazolin-4-ol(23 mg, 0.09 mmol), 4-(2-methoxy-phenyl)-piperidine hydrochloride (23mg, 0.1 mmol) and BOP (60 mg, 0.14 mmol) in ACN (10 mL) was added DBU(68 mg, 0.45 mmol), till the suspension was clear, then the mixture wasstirred at rt overnight. The mixture was concentrated and purified byprep-TLC (DCM/MeOH=20/1) to afford{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-5-yl}-methyl-propyl-amine(46.9 mg, yield: 100%) as yellow solid. ¹H NMR (400 MHz, CDCl₃):δ=7.64-7.43 (m, 2H), 7.22-7.20 (m, 1H), 7.08-6.88 (m, 4H), 5.28 (d,J=14.8 Hz, 1H), 3.84 (s, 3H), 3.76-3.74 (m, 1H), 3.71-3.59 (m, 1H),3.55-3.22 (m, 3H), 3.00-2.95 (m, 3H), 2.77-2.75 (m, 1H), 2.54-2.51 (m,1H), 2.08-2.03 (m, 1H), 1.81- 1.78 (m, 3H), 1.68-1.64 (m, 2H), 1.31-1.22(m, 3H), 1.06-1.04 (m, 2H), 0.69-0.67 (m, 2H). MS: m/z 432.3 (M+H⁺)

Example 132: Preparation of2-((2-cyclopropyl-5-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.56-7.48 (m, 2H), 7.23-7.17 (m, 2H), 6.95(t, J=7.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.20 (d, J=12.4 Hz, 2H), 3.85(s, 3H), 3.74 (t, J=5.2 Hz, 2H), 3.25 (t, J=5.6 Hz, 2H), 3.10 (t, J=12.4Hz, 2H), 2.88 (s, 3H), 2.16-2.13 (m, 1H), 1.95-1.82 (m, 4H), 1.19-1.14(m, 2H), 1.00-0.95 (m, 2H). MS: m/z 451.2 (M+H⁺)

Example 133: Preparation of2-((2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol

The title compound was prepared as described in example2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.25-7.08 (m, 2H), 7.05 (dd, J=13.2, 2.0 Hz,1H), 6.97 (t, J=8.0 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.71 (s, 1H), 4.35(d, J=12.4 Hz, 2H), 3.90-3.85 (m, 5H), 3.53 (t, J=5.2 Hz, 2H), 3.29-3.25(m, 1H), 3.13 (t, J=12.4 Hz, 2H), 2.78 (s, 3H), 2.26-2.23 (m, 1H),1.95-1.82 (m, 5H), 1.19-1.14 (m, 2H), 1.00-0.95 (m, 2H). MS: m/z 451.2(M+H⁺)

Example 134: Preparation of2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methyl-N-(2-morpholinoethyl)pyrido[3,4-d]pyrimidin-6-amine

The title compound was prepared as described in example2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.90 (s, 1H), 7.20 (d, J=8.0 Hz, 2H),6.98-6.88 (m, 2H), 6.50 (s, 1H), 4.43 (d, J=12.4 Hz, 2H), 3.86-3.80 (m,5H), 3.71-3.65 (m, 4H), 3.31-3.28 (m, 1H), 3.19-3.12 (m, 2H), 3.09 (s,3H), 2.62-2.51 (m, 6H), 2.20-2.18 (m, 1H), 2.00-1.84 (m, 4H), 1.15-1.12(m, 2H), 1.00-0.87 (m, 2H). MS: m/z 503.3 (M+H⁺)

Example 135: Preparation of2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methyl-N-propylquinazolin-7-amine

The title compound was prepared as described in example2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.63 (d, J=9.3 Hz, 1H), 7.28-7.15 (m, 3H),7.00-6.82 (m, 3H), 4.65 (d, J=12.4 Hz, 2H), 3.87 (s, 3H), 3.46-3.30 (m,5H), 3.11 (s, 3H), 2.50-2.40 (m, 1H), 2.05-1.97 (m, 2H), 1.90-1.62 (m,4H), 1.28- 1.13 (m, 4H), 0.97 (t, J=7.5 Hz, 3H). MS: m/z 431.3 (M+H⁺)

Example 136: Preparation of2-((2-(cyclopropylethynyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol

The title compound was prepared as described for2-{2-Dimethylamino-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylamino}-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.76 (d, J=8.8 Hz, 1H), 7.36 (dd, J=9.2, 2.8Hz, 1H), 7.27-7.20 (m, 2H), 6.99-6.88 (m, 3H), 4.45-4.39 (m, 2H),3.90-3.86 (m, 5H), 3.60-3.55 (m, 2H), 3.71-3.59 (m, 1H), 3.21-3.15 (m,3H), 3.07 (s, 3H), 2.05-1.90 (m, 3H), 1.57-1.49 (m, 1H), 1.00-0.86 (m,4H). MS: m/z 457.2 (M+H⁺)

Example 137: Preparation of2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol

To a stirred solution of 6-chloro-pyridin-3-ylamine (10 g, 7.7 mmol) inDCM (150 mL) was added Boc₂O (18.5 g, 8.46 mmol) dropwised at 0° C. andDMAP (0.5 g, 4 mmol), Et₃N (16.3 g, 16.2 mmol) as follows. The mixturewas allowed to warm to room temperature and stirred for 18 hours. Thereactaction solution was concentrated under reduced pressure to dryness.The residue was purified by silica gel chromatography (from PE toPE/EA=20/1) to give (13.0 g, yield: 76%) of(6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester as yellow solid.NMR (300 MHz, CDCl₃): δ=8.21 (brs, 1H), 8.45 (s, 1H), 7.91 (d, J=6.3 Hz,1H), 7.49 (d, J=8.4 Hz, 1H), 1.47-1.37 (m, 9H).

To a stirred solution of (6-chloro-pyridin-3-yl)-carbamic acidtert-butyl ester (5.6 g, 24.6 mmol) in THF (100 mL) was added n-BuLi (29mL, 74.0 mmol) dropwise at −78° C. The mixture was stirred at thistemperature for 1 hors. Then the vessel was charged with carbon dioxideto a pressure of 0.7 Mbar and stirred at −40° C. for 10 min. Afterwarmed to room temperature, the mixture was poured into the ice waterand the pH value was adjusted to pH=3. The aqueous phase was extractedwith EA (100 mL×2). The combined organic layers were washed with brine(30 mL×2), dried over anhydrous Na₂SO₄ and filtered. The filtrate wasevaporated in vacuum to give the product (crude, 8.0 g) of5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid as red oil.

To a stirred solution of5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid (crude, 8.0 g) inmethanol (50 mL) was added H₂SO₄ (5.0 mL). The mixture was then heatedto reflux overnight. The reaction was cooled to room temperature and wasconcentrated in vacuum. The residue was diluted with water. The aqueousmixture was neutralized with sat. NaHCO₃ to pH=8 and extracted with EA(100 mL×2). The combined organic layers were washed with brine (50 mL),dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated invacuum to residue, which was purified by silica gel chromatography (fromPE to PE/EA=2/1) to give (1.1 g, two steps of yield: 24%) of5-amino-2-chloro-isonicotinic acid methyl ester as yellow solid.

To a stirred solution of (5-amino-2-chloro-isonicotinic acid methylester (1.3 g, 7 mmol) in DCM (30 mL) was added Et₃N (1.4 g, 14 mmol) andcyclopropanecarbonyl chloride (1.1 g, 10.5 mmol) at 0° C. The mixturewas stirred at room temperature overnight. The mixture was evaporated invacuum. The residue was diluted with water (50 mL). The aqueous phasewas extracted with EA (80 mL×2). The extracts were washed with water,dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated invacuum to residue, which was purified by silica gel chromatography (fromPE to PE/EA=10/1) to give (1.0 g, yield: 56%) of2-chloro-5-(cyclopropanecarbonyl-amino)-isonicotinic acid methyl esteras yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=10.56 (brs, 1H), 8.79 (s,1H), 7.23 (s, 1H), 3.82 (s, 3H), 1.87-1.80 (m, 3H), 0.94-0.83 (m, 4H).

A suspension of 2-chloro-5-(cyclopropanecarbonyl-amino)-isonicotinicacid methyl ester (1.0 g, 3.9 mmol) in NH₃.H₂O (10 mL) was heated toreflux for 3 days. The reaction was cooled to room temperature and wasconcentrated to dryness in vacuum. The residue (300 mg, yield: 20%) waswashed with methanol and used directly in next step without furtherpurification.

To a stirred solution of6-chloro-2-cyclopropyl-3H-pyrido[3,4-d]pyrimidin-4-one (200 mg, 0.9mmol) in acetonitrile (8 mL) was added DIEA (1.24 g, 10.9 mmol) and4-(2-methoxy-phenyl)-piperidine (1.12 g, 4.9 mmol). The mixture wasstirred at room temperature overnight. The mixture was evaporated invacuum. The residue (180 mg, yield: 51%) was washed with methanol andused directly in next step without further purification.

To a stirred solution of6-chloro-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido-[3,4-d]pyrimidine(60 mg, 0.15 mmol) in NMP (1 mL) was added DIEA (40 mg, 0.3 mmol) and4-(2-methoxy-phenyl)-piperidine (68 mg, 0.9 mmol). The mixture washeated at 170° C. in a microwave for 5 hours. The residue was dilutedwith EA (200 mL) and washed with water, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was evaporated in vacuum to residue, which waspurified by pre-HPLC (MeCN/H₂O from 5/100 to 95/100) to give (25.8 mg,yield: 40%) of2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido-[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanolas yellow oil. ¹H NMR (400 MHz, CDCl₃): δ=8.88 (s, 1H), 7.28-7.25 (m,2H), 7.01-6.94 (m, 1H), 6.62 (s, 1H), 4.49-4.46 (m, 2H), 3.95-3.89 (m,7H), 3.38-3.32 (m, 1H), 3.25-3.16 (m, 5H), 2.22-2.18 (m, 1H), 2.05-1.87(m, 4H), 1.20-1.17 (m, 2H), 1.03-0.99 (m, 2H). MS: m/z 434.2 (M+H⁺)

Example 138: Preparation of2-((2-cyclopropyl-4-(4-(3-methoxythiophen-2-yl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.57-7.52 (m, 1H), 7.33 (dd, J=8.8, 2.8 Hz,1H), 7.04 (d, J=5.6 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.85 (d, J=5.2 Hz,1H), 4.34-4.30 (m, 2H), 3.88-3.83 (m, 5H), 3.56-3.53 (m, 2H), 3.25-3.23(m, 1H), 3.11 (t, J=12.4 Hz, 2H), 3.04 (s, 3H), 2.09-2.00 (m, 3H),1.93-1.85 (m, 2H), 1.17-1.13 (m, 2H), 0.99-0.95 (m, 2H). MS: m/z 439.2(M+H⁺)

Example 139: Preparation of2-((4-(4-cyclohexylpiperidin-1-yl)-2-(1-fluorocyclopropyl)quinazolin-6-yl)(methyl)amino)ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.89 (d, J=9.2 Hz, 1H), 7.38 (dd, J=9.2, 2.8Hz, 1H), 6.93 (d, J=2.8 Hz, 1H), 4.24 (d, J=12.8 Hz, 2H), 3.88 (t, J=5.6Hz, 2H), 3.57 (t, J=5.6 Hz, 2H), 3.07 (s, 3H), 2.93 (t, J=12.4 Hz, 2H),1.83-0.98 (m, 21H). MS: m/z 427.3 (M+H⁺)

Example 140: Preparation of2-(4-{2-cyclopropyl-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-yl}-piperazin-1-yl)-cyclopentanol

The title compound was prepared as described for2-[(2-cyclopropyl-4-{[(2-methoxy-phenyl)-methyl-amino]-cyclopentylamino}-quinazolin-6-yl)-methyl-amino]-ethanol.¹HNMR (300 MHz, CD₃OD): δ=7.65 (d, J=9.3 Hz, 1H), 7.40 (dd, J=9.3, 2.7Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.13-3.11 (m, 1H), 3.77-3.73 (m, 2H),3.65-3.51 (m, 4H), 3.36-3.31 (m, 2H), 3.04 (s, 3H), 2.84-2.68 (m, 4H),2.52-2.50 (m, 1H), 2.10-1.93 (m, 3H), 1.69-1.62 (s, 3H), 1.12-1.11 (m,1H), 1.09-1.07 (m, 2H), 0.98-0.94 (m, 2H). MS: m/z 412.2 (M+H⁺)

Example 141: Preparation of2-{4-[2-cyclopropyl-6-(methyl-propyl-amino)-quinazolin-4-yl]-piperazin-1-yl}-cyclopentanol

The title compound was prepared as described for2-[(2-cyclopropyl-4-{[2-(2-methoxy-phenyl)-methyl-amino]-cyclopentylamino}-quinazolin-6-yl)-methyl-amino]-ethanol.¹HNMR (400 MHz, CD₃OD): δ=7.61 (d, J=9.2 Hz, 1H), 7.36 (dd, J=9.2, 2.4Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 4.15-4.12 (m, 1H), 3.63 (brs, 4H),3.36-3.32 (m, 2H), 2.99-2.64 (m, 4H), 2.54-2.51 (m, 1H), 2.12-2.08 (m,1H), 1.99-1.93 (m, 2H), 1.73-1.43 (m, 5H), 1.12-1.10 (m, 1H), 0.97-0.95(m, 2H), 0.95-0.93 (m, 5H). MS: m/z 410.2 (M+H⁺)

Example 142: Preparation of2-(4-{2-cyclopropyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-quinazolin-4-yl}-piperazin-1-yl)-cyclopentanol

The title compound was prepared as described for2-[(2-cyclopropyl-4-{2-[(2-methoxy-phenyl)-methyl-amino]-cyclopentylamino}-quinazolin-6-yl)-methyl-amino]-ethanol.¹HNMR (400 MHz, CD₃OD): δ=7.72 (d, J=9.2 Hz, 1H), 7.52 (dd, J=9.2, 2.4Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 4.19-4.17 (m, 1H), 3.87 (brs, 4H),3.73-3.65 (m, 6H), 3.10 (s, 3H), 3.00-2.85 (m, 4H), 2.67-2.56 (m, 7H),2.13-1.97 (m, 3H), 1.75-1.53 (m, 4H), 1.20-1.07 (m, 4H). MS: m/z 481.2(M+H⁺)

Example 143: Preparation of4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-dimethyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.55 (d, J=6.4 Hz, 2H), 7.88 (d, J=9.2 Hz,1H), 7.50-7.24 (m, 6H), 6.96-6.89 (m, 3H), 4.52 (d, J=12.0 Hz, 2H), 3.96(s, 3H), 3.28-3.26 (m, 3H), 3.06 (s, 6H), 2.02 (bs, 4H). MS: m/z 439.2(M+H⁺).

Example 144: Preparation of2-({4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.53 (d, J=7.2 Hz, 2H), 7.86 (d, J=8.8 Hz,1H), 7.49-7.37 (m, 4H), 7.28-7.20 (m, 2H), 6.98-6.90 (m, 3H), 4.51 (d,J=12.4 Hz, 2H), 3.87 (brs, 5H), 3.58-3.56 (m, 2H), 3.34-3.23 (m, 3H),3.04 (s, 3H), 2.03-1.98 (m, 4H). MS: m/z 469.2 (M+H⁺).

Example 145: Preparation of(2-methoxy-ethyl)-{4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-methyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.60 (d, J=6.6 Hz, 2H), 7.90 (d, J=8.4 Hz,1H), 7.52-7.38 (m, 4H), 7.31-7.22 (m, 2H), 7.01-6.91 (m, 3H), 4.52 (d,J=12.9 Hz, 2H), 3.89 (s, 3H), 3.65 (s, 4H), 3.39-3.23 (m, 6H), 3.12 (s,3H), 2.06-1.98 (m, 4H). MS: m/z 483.2 (M+H⁺).

Example 146: Preparation of{4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-methyl-propyl-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.57 (d, J=6.4 Hz, 2H), 7.91 (d, J=6.8 Hz,1H), 7.50-7.26 (m, 6H), 7.00-6.93 (m, 3H), 4.54 (d, J=11.2 Hz, 2H), 3.90(s, 3H), 3.43-3.28 (m, 5H), 3.09 (s, 3H), 2.06 (brs, 4H), 1.71-1.70 (m,2H), 1.00 (t, 3H). MS: m/z 467.2 (M+H⁺).

Example 147: Preparation of{4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=8.60 (d, J=6.6 Hz, 2H), 8.00 (d, J=9.2 Hz,1H), 7.52-7.36 (m, 4H), 7.29-7.22 (m, 2H), 7.01-6.91 (m, 3H), 4.57 (d,J=12.6 Hz, 2H), 3.89 (s, 3H), 3.75-3.64 (m, 6H), 3.41-3.24 (m, 3H), 3.10(s, 3H), 2.76-2.51 (m, 6H), 2.06-1.99 (m, 4H). MS: m/z 538.3 (M+H⁺).

Example 148: Preparation of{[2-cyclopropyl-4-(5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.64 (d, J=8.8 Hz, 1H), 7.24-7.23 (m, 1H),7.18-7.14 (m, 1H), 7.01 (s, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.70 (d, J=8.0Hz, 1H), 4.80 (brs, 2H), 3.91-3.88 (m, 4H), 3.83 (s, 3H), 3.57-3.54 (m,2H), 3.09-3.07 (m, 2H), 3.05 (s, 3H), 2.21-2.17 (m, 1H), 1.17-1.16 (m,2H), 0.98-0.95 (m, 2H). MS: m/z 405.2 (M+H⁺).

Example 149: Preparation of2-{[2-cyclopropyl-4-(4-methoxy-1,3-dihydro-isoindol-2-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.82 (d, J=10.0 Hz, 1H), 7.42 (s, 1H),7.33-7.29 (m, 2H), 7.01 (s, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 5.22 (d, J=10.8 Hz, 2H), 3.95-3.89 (m, 2H), 3.87 (s, 3H),3.59-3.57 (m, 2H), 3.09 (s, 3H), 2.42-2.38 (m, 1H), 1.25-1.22 (m, 2H),1.06-1.04 (m, 2H). MS: m/z 391.2 (M+H⁺).

Example 150: Preparation of2-{[2-cyclopropyl-4-(6-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=¹H NMR (400 MHz, CDCl₃): δ=7.78 (d, J=9.0 Hz,1H), 7.31-7.28 (m, 1H), 7.13-7.09 (m, 1H), 6.96 (s, 1H), 6.77 (d, J=8.0Hz, 2H), 3.89-3.84 m, 6H), 3.82 (s, 3H), 3.57-3.54 (m, 2H), 3.27-3.24(m, 2H), 3.16-3.13 (m, 2H), 3.06 (s, 3H), 2.20-2.18 (m, 1H), 1.16-1.12(m, 2H), 0.98-0.95 (m, 2H). MS: m/z 419.2 (M+H⁺).

Example 151: Preparation of2-[(2-cyclopropyl-4-{2-[(2-methoxy-phenyl)-methyl-amino]-cyclopentylamino}-quinazolin-6-yl)-methyl-amino]-ethanol

To a mixture of 6-oxa-bicyclo[3.1.0]hexane (2.0 g, 23.8 mmol) with2-methoxy-phenylamine (2.34 g, 19.0 mmol) was added ZrCl₄ (500 mg), itwas then stirred at r.t overnight. The resultant was diluted with EA (50mL) and the resulting solid was filtered. The filtrate was concentratedin vacuum and the residue was purified by flash column (EA in PE: 0 to30%) to afford 2-[(2-methoxy-phenyl)-methyl-amino]-cyclopentanol (2.2 g,yield: 53%) as a white solid.

The preparation of 2-((2-methoxyphenyl)(methyl)amino)cyclopentanol viareductive amination is similar to2-cyclopropyl-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol.

To a solution of 2-[(2-methoxy-phenyl)-methyl-amino]-cyclopentanol (2.2g, 9.95 mmol) in DCM was added methanesulfonyl chloride (1.24 g, 11mmol) and the mixture was stirred at r.t. for 1 hour. The reaction wasquenched with water (100 mL) and the mixture was extracted with EA (100mL). The extracts were dried over Na₂SO₄. The organic layer wasconcentrated in vacuum and the crude for the next step without furtherpurification.

The crude product was dissolved in DMF (40 mL) and then NaN₃ (715 mg, 11mmol) was added. The reaction solution was heated to 90° C. and stirredovernight. The resultant was contracted directly to remove most of DMF.The remaining residue was then dissolved in MeOH (50 mL) and then Pd/C(500 mg) was added. It was degassed with H₂ for several times andstirred at r.t. under H₂ balloon pressure until LC/MS showed reactionwas completed. The resultant was filttered to remove Pd/C and thefiltrate was purified by flash column (EA im PE: 0 to 50%) to afforddesired intermediateN-(2-methoxy-phenyl)-N-methyl-cyclopentane-1,2-diamine (1.1 g, yield:50%) as a white solid.

To a solution of 6-bromo-2-cyclopropyl-quinazolin-4-ol (2 g, 7.6 mmol)in DMSO (20 mL) were added 2-amino-ethanol (693 mg, 11.4 mmol), CuI (500mg), proline (500 mg) and Cs₂CO₃ (6.4 g, 16.7 mmol). The mixture wasstirred at 90° C. overnight under the protection of N₂. The resultantwas purified by pre-HPLC to give2-cyclopropyl-6-(2-hydroxy-ethylamino)-quinazolin-4-ol (1.4 g, yield:75%) as a white solid.

To a solution of 2-cyclopropyl-6-(2-hydroxy-ethylamino)-quinazolin-4-ol(1.4 g, 5.7 mmol) in MeOH (20 mL) was added formalin (3 mL) and thenNaCNBH₃ (28.5 mmol). The mixture was stirred at r.t. overnight. Theresultant was concentrated to dryness and the residue was purified byflash column (C₁₈-silica ACN in water: 5% to 95%) to give2-cyclopropyl-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol product(1.2 g, yield: 81%) as a white solid.

To a solution of N-(2-methoxy-phenyl)-N-methyl-cyclopentane-1,2-diamine(100 mg, 0.45 mmol) in ACN (20 mL) was added2-cyclopropyl-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol (117mg, 0.45 mmol), BOP (298 mg, 0.67 mmol) and DBU (0.5 mL). The mixturewas stirred at room temperature overnight. The solvent was removed andthe residue was dissolved in EA (50 mL). The mixture was washed withbrine (30 mL×2). The organic layer was separated and dried overanhydrous Na₂SO₄ The solvent was removed and the residue was purified bypre-HPLC to give2-[(2-cyclopropyl-4-{2-[(2-methoxy-phenyl)-methyl-amino]-cyclopentylamino}-quinazolin-6-yl)-methyl-amino]-ethanol(80 mg, yield: 38%) as a white solid. ¹HNMR (400 MHz, CD₃OD): δ=7.38 (s,2H), 6.86 (s, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.63-6.59 (m, 2H), 6.47-6.43(m, 1H), 4.87-4.81 (m, 1H), 4.10-4.08 (m, 1H), 3.66-3.64 (m, 5H),3.51-3.48 (m, 2H), 2.99 (s, 3H), 2.65 (s, 3H), 2.04-1.99 (m, 2H),1.92-1.88 (m, 1H), 1.98-1.78 (m, 2H), 1.67-1.63 (m, 1H), 1.29-1.14 (m,4H). MS: m/z 462.2 (M+H⁺).

Example 152: Preparation of2-cyclopropyl-N4-{2-[(2-methoxy-phenyl)-methyl-amino]-cyclopentyl}-N6-methyl-N6-propyl-quinazoline-4,6-diamine

The title compound was prepared as described for2-[(2-cyclopropyl-4-{2-[(2-methoxy-phenyl)-methyl-amino]-cyclopentylamino}-quinazolin-6-yl)-methyl-amino]-ethanol.¹H NMR (400 MHz, CD₃OD): δ=7.49 (d, J=9.2 Hz, 1H), 7.31 (dd, J=9.2, 2.4Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.81 (d, J=4.0 Hz, 2H), 6.71 (d, J=2.4Hz, 1H), 6.65-6.61 (m, 1H), 4.78-4.71 (m, 1H), 4.07-4.03 (m, 1H), 3.79(s, 3H), 3.40-3.37 (m, 2H), 2.97 (s, 3H), 2.79 (s, 3H), 2.23-2.19 (m,1H), 2.06-2.02 (m, 1H), 1.93-1.76 (m, 4H), 1.67-1.60 (m, 3H), 1.19-1.11(m, 2H), 0.97-0.94 (m, 5H). MS: m/z 460.3 (M+H⁺).

Example 153: Preparation of2-({2-cyclopropyl-4-[3-(2-methoxy-phenylamino)-pyrrolidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

To a mixture of 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester(1.0 g, 5.37 mmol), 1-bromo-2-methoxy-benzene (1.2 g, 6.45 mmol) andCs₂CO₃ (3.5 g, 10.8 mmol) in anhydrous toluene (50 mL) was added BINAP(673 mg, 1.1 mmol) and Pd(OAc)₂ (121 mg, 0.54 mmol). The mixture wasrefluxed under N₂ for 16 h. The mixture was cooled to rt, diluted withDCM (15 mL) and filtered, the filtraction was concentrated, purified bysilica gel chromatography (from PE to PE/EA=50/1-20/1-5/1) to give (761mg, yield: 48%) of 3-(2-methoxy-phenylamino)-pyrrolidine-1-carboxylicacid tert-butyl ester as yellow liquid. ¹H NMR (400 MHz, CDCl₃):δ=6.89-6.86 (m, 1H), 6.79-6.77 (m, 1H), 6.71-6.69 (m, 1H), 6.62-6.60 (m,1H), 4.29-4.28 (m, 1H), 4.04-4.01 (m, 1H), 3.84 (s, 3H), 3.76-3.67 (m,1H), 3.54- 3.44 (m, 2H), 3.30-3.20 (m, 1H), 2.24-2.15 (m, 1H), 1.93-1.89(m, 1H), 1.46 (s, 9H).

To a solution of 3-(2-methoxy-phenylamino)-pyrrolidine-1-carboxylic acidtert-butyl ester (761 mg, 2.6 mmol) in EA (10 mL) was added HCl/dioxane(10 mL), then the mixture was stirred at rt for 5 h. The mixture wasconcentrated to give (2-methoxy-phenyl)-pyrrolidin-3-yl-aminehydrochloride (700 mg, yield: 100%) as a green solid.

A suspension of[1-(6-bromo-2-cyclopropyl-quinazolin-4-yl)-pyrrolidin-3-yl]-(2-methoxy-phenyl)-amine(320 mg, 0.73 mmol) in (Boc)₂O (10 mL) was stirred at 90° C. overnight.The reaction mixture was concentrated and purified by silica gelchromatography (from PE to PE/EA=20/1-10/1-5/1) to give crude product,then further purified by prep-HPLC to afford (364 mg, yield: 92%) of[1-(6-bromo-2-cyclopropyl-quinazolin-4-yl)-pyrrolidin-3-yl]-(2-methoxy-phenyl)carbamic acid tert-butyl ester as white solid. ¹HNMR (400 MHz, CDCl₃):δ=8.09-8.04 (m, 1H), 7.67-7.65 (m, 1H), 7.60-7.56 (m, 1H), 7.29-7.24 (m,1H), 7.05-7.04 (m, 1H), 6.93-6.79 (m, 2H), 5.13-5.06 (m, 1H), 4.06-4.04(m, 1H), 3.74- 3.58 (m, 5H), 2.25-2.23 (m, 1H), 1.61 (s, 4H), 1.31-1.29(m, 9H), 1.11-1.05 (m, 2H), 0.96-0.91 (m, 2H).

To a solution of[1-(6-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-cyclopropyl-quinazolin-4-yl)-pyrrolidin-3-yl]-(2-methoxy-phenyl)-carbamicacid tert-butyl ester (50 mg, 0.08 mmol) in DCM (2 mL) was added TFA (2mL), the reaction mixture was stirred at rt overnight. The reactionmixture was concentrated, purified by prep-HPLC (NH₄HCO₃) to afford (3.1mg, yield: 30%) of2-({2-cyclopropyl-4-[3-(2-methoxy-phenylamino)-pyrrolidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanolas yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=7.88 (d, J=8.4 Hz, 1H), 7.31(s, 1H), 7.25-7.23 (m, 1H), 6.90-6.88 (m, 1H), 6.81-6.74 (m, 2H), 6.66(d, J=7.2 Hz, 1H), 4.33-4.20 (m, 5H), 3.95-3.90 (m, 1H), 3.84-3.82 (m,5H), 3.52-3.49 (m, 2H), 3.01 (s, 3H), 2.37-2.02 (m, 4H), 1.19-0.88 (m,4H). MS: m/z 434.2 (M+H⁺)

Example 154: Preparation of2-((2-cyclopropyl-4-((1-(2-methoxyphenyl)pyrrolidin-3-yl)amino)quinazolin-6-yl)(methyl)amino)ethanol

The title compound was prepared as described for2-({2-cyclopropyl-4-[3-(2-methoxy-phenylamino)-pyrrolidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.58 (d, J=9.2 Hz, 1H), 7.18 (dd, J=9.2, 2.4Hz, 1H), 6.92-6.78 (m, 5H), 6.31 (brs, 1H), 4.92-4.88 (m, 1H), 3.85-3.80(m, 5H), 3.63-3.52 (m, 4H), 3.46-3.40 (m, 1H), 3.27-3.23 (m, 1H), 3.00(s, 3H), 2.48- 2.42 (m, 1H), 2.19-2.08 (m, 2H), 1.27-1.23 (m, 2H),0.98-0.93 (m, 2H). MS: m/z 434.2 (M+H⁺)

Example 155: Preparation of2-cyclopropyl-N4-(1-(2-methoxyphenyl)pyrrolidin-3-yl)-N6-methyl-N6-propylquinazoline-4,6-diamine

The title compound was prepared as described for2-({2-cyclopropyl-4-[3-(2-methoxy-phenylamino)-pyrrolidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.82-7.76 (m, 1H), 7.29-7.26 (m, 2H),6.94-6.80 (m, 4H), 6.49 (brs, 1H), 4.94-4.90 (m, 1H), 3.87 (s, 3H),3.63-3.58 (m, 2H), 3.50-3.47 (m, 1H), 3.36 (t, J=11.6 Hz, 2H), 3.27-3.23(m, 1H), 3.01 (s, 3H), 2.50-2.42 (m, 1H), 2.08-2.05 (m, 1H), 1.67-1.58(m, 3H), 1.27-1.23 (m, 2H), 0.98-0.95 (m, 2H), 0.93 (t, J=7.6 Hz, 3H).MS: m/z 432.2 (M+H⁺).

Example 156: Preparation of Methyl2-(2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-methylpyrimidin-5-yl)acetate

Thiourea (7.1 g, 93.5 mmol) and 2-acetyl-succinic acid 4-ethyl ester1-methyl ester (20.0 g, 92.6 mmol) were added at room temperature to asolution of sodium (4.3 g, 186.9 mmol) in methanol (300 mL) and themixture is stirred under N₂ reflux for 18 h. After cooling, theprecipitate was filtered off and added with stirring to a HCl (12 N) at0° C. The white precipitate was filtered, washed with water and dried togive of title compound as a white power (7.0 g, yield: 37%). MS: m/z200.7 (M+H⁺).

To a stirred solution of(6-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetic acid(7.0 g, 35.0 mmol) in methanol (150 mL) was added H₂SO₄ (7.0 mL). Themixture was then heated to reflux overnight. The reaction was cooled toroom temperature and was concentrated. The residue was washed with waterand EA. and the solid was evaporated in vacuum to dryness to afford (6.1g, yield: 81.3%) of(6-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetic acidmethyl ester as a white solid.

To a stirred solution of(6-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetic acidmethyl ester (6.1 g, 28.5 mmol) in POCl₃(100 mL). The mixture was thenheated to reflux for 2 days. The reaction was cooled to room temperatureand was concentrated in vacuum. and added into ice water (150 mL)dropwise. The aqueous mixture was neutralized with sat. NaHCO₃ to pH=8and extracted with EA (150 mL×2). The combined organic layers werewashed with brine (30 mL×2), dried over anhydrous Na₂SO₄ and filtered.The filtrate was evaporated in vacuum to residue, which was purified bysilica gel chromatography (from PE to PE/EA=5/1) to give (2.7 g, yield:39.1%) of (2,4-dichloro-6-methyl-pyrimidin-5-yl)-acetic acid methylester as yellow solid. MS: m/z 235.1 (M+H⁺).

To a stirred solution of (2,4-dichloro-6-methyl-pyrimidin-5-yl)-aceticacid methyl ester (1.15 g, 4.9 mmol) in ethanol (20 mL) was added DIEA(1.26 g, 9.8 mmol) and 4-(2-Methoxy-phenyl)-piperidine (1.0 g, 4.4mmol). The mixture was stirred at room temperature for overnight. Themixture was evaporated in vacuum to residue, which was purified bysilica gel chromatography (PE/EA from 10/1 to 5/1) to give 950 mg(yield: 50%) of{2-chloro-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester (450 mg) MS Calculated 389.1, observed [M+H]=390.2.and{4-chloro-2-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester (400 mg) as yellow solid. ¹H NMR (400 MHz, CDCl₃):δ=7.31-7.28 (m, 1H), 7.24-7.19 (m, 1H), 6.97-6.91 (m, 2H), 4.95 (d,J=13.6 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.72 (s, 2H), 3.33-3.21 (m,1H), 3.00 (t, J=12.0 Hz, 2H), 2.40 (s, 3H), 1.93-1.90 (m, 2H), 1.91-1.63(m, 2H). MS: m/z 390.5 (M+H⁺)

To a mixture of{2-chloro-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester (500 mg, 1.3 mmol), cyclopropane boronic acid (280 mg,3.25 mmol) and K₃PO₄ (827 mg, 3.9 mmol) in THF (30 mL) was addedPd(dppf)Cl₂ (150 mg, 0.18 mmol). The mixture was stirred at 90° C. underN₂ for 18 h, cooled to room temperature and evaporated under reducedpressure to dryness. The residue was diluted with EA (200 mL) and washedwith water, dried over anhydrous Na₂SO₄, filtered. The filtrate wasevaporated in vacuum to residue, which was purified by silica gelchromatography (from PE to PE/EA=20/1) to give (210 mg, yield: 40%) of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester as yellow solid. ¹H NMR (300 MHz, CDCl₃): δ=7.28-7.18(m, 2H), 6.95 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 3.84 (s, 3H),3.74 (s, 3H), 3.65-3.62 (m, 3H), 3.19-3.11 (m, 1H), 2.90 (t, J=9.0 Hz,1H), 2.34 (s, 3H), 2.13-2.05 (m, 1H), 1.90-1.72 (m, 4H), 1.09-0.95 (m,4H). MS: m/z 396.3 (M+H⁺).

Example 157: Preparation of2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamide

A mixture of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester (1.0 g, 6.4 mmol) in THF (10 mL), and LiOH (0.61 g,25.6 mmol) in water (2 mL) was added dropwise. The reaction mixture wasstirred at room temperature overnight. The mixture was acidified with 1NHCl to pH=2. The suspension was filtered and the cake was washed withwater (10 mL×2), then evaporated in vacuum to dryness to give (130 mg,yield: 48%) of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid as yellow solid.

To a stirred solution of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid (60 mg, 0.15 mmol) in DMF (2 mL) was added HATU (90 mg, 0.24 mmol)and dimethyl-amine (0.15 mL, 0.3 mmol). The mixture was stirred at roomtemperature overnight. The mixture was evaporated in vacuum to residue,which was purified by pre-HPLC (MeCN/H₂O from 5/100 to 95/100) to give(30 mg, yield: 47%) of2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamideas a white solid. ¹H NMR (400 MHz, CDCl₃): δ=7.26-7.21 (m, 2H), 6.98 (t,J=7.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 3.87 (s, 3H), 3.71-3.60 (m, 4H),3.24-3.11 (m, 4H), 3.22-2.95 (m, 5H), 2.53 (s, 3H), 2.14-2.09 (m, 1H),1.92 (d, J=11.2 Hz, 2H), 1.80-1.76 (m, 2H), 1.13-0.95 (m, 4H). MS: m/z409.3 (M+H⁺)

Example 158: Preparation of2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N-methyl-N-propyl-acetamide

The title compound was prepared as described for2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamide.¹H NMR (400 MHz, CDCl₃): δ=7.25-7.22 (m, 2H), 6.98 (t, J=7.6 Hz, 1H),6.91 (d, J=8.4 Hz, 1H), 3.87 (s, 3H), 3.67-3.62 (m, 4H), 3.44-3.32 (m,2H), 3.18-3.11 (m, 3H), 3.02-2.95 (m, 3H), 2.35 (s, 3H), 2.13-2.09 (m,1H), 1.92-1.55 (m, 6H), 1.12-1.10 (m, 2H), 0.98-0.88 (m, 4H). MS: m/z437.3 (M+H⁺)

Example 159: Preparation of2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N-(2-hydroxy-ethyl)-N-methyl-acetamide

The title compound was prepared as described for2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamide.¹H NMR (400 MHz, CDCl₃): δ=7.29-7.24 (m, 2H), 7.00-6.90 (m, 2H),387-3.79 (m, 5H), 3.66-3.59 (m, 5H), 3.19 (s, 3H), 3.09-2.96 (m, 3H),2.35 (s, 3H), 2.13-2.10 (m, 1H), 1.93-1.90 (m, 2H), 1.82-1.74 (m, 3H),1.17-1.13 (m, 2H), 0.97- 0.92 (m, 2H). MS: m/z 4329.3 (M+H⁺)

Example 160: Preparation of2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-1-phenyl-ethanone

The title compound was prepared as described for2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamide.¹H NMR (400 MHz, CDCl₃): δ=8.04 (brs, 1H), 7.48 (d, J=8.0 Hz, 2H),7.36-7.31 (m, 2H), 7.26-7.12 (m, 3H), 6.98 (t, J=7.6 Hz, 1H), 6.92 (d,J=8.4 Hz, 1H), 3.86 (s, 3H), 3.74-3.70 (m, 4H), 3.20-3.09 (m, 3H), 2.53(s, 3H), 2.17-2.14 (m, 1H), 2.05-1.89 (m, 4H), 1.17-1.14 (m, 2H),1.05-1.02 (m, 2H). MS: m/z 457.2 (M+H⁺)

Example 161: Preparation of{4-cyclopropyl-2-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester

The title compound was prepared as described for2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamide.¹H NMR (400 MHz, CDCl₃): δ=7.25-7.19 (m, 2H), 6.96 (t, J=7.6 Hz, 1H),6.92 (d, J=8.0 Hz, 1H), 4.94 (d, J=13.2 Hz, 2H), 3.89 (s, 3H), 3.74-3.62(m, 5H), 3.26-3.20 (m, 1H), 2.94-2.88 (m, 2H), 2.41 (s, 3H), 2.03-1.99(m, 1H), 1.91- 1.88 (m, 2H), 1.71-1.61 (m, 2H), 1.17-1.13 (m, 2H),0.97-0.92 (m, 2H). MS: m/z 396.2 (M+H⁺)

Example 162: Preparation of2-{4-cyclopropyl-2-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N-methyl-N-propyl-acetamide

The title compound was prepared as described in example2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamide.¹H NMR (400 MHz, CDCl₃): δ=7.24-7.20 (m, 2H), 6.97 (t, J=7.6 Hz, 1H),6.91 (d, J=8.0 Hz, 1H), 4.93 (d, J=13.2 Hz, 2H), 3.89 (s, 3H), 3.73 (d,J=10.0 Hz, 1H), 3.45-3.40 (m, 2H), 3.26-3.20 (m, 1H), 3.15-3.01 (m, 3H),2.90 (t, J=12.0 Hz, 2H), 2.33 (s, 3H), 1.89-1.85 (m, 3H), 1.73-1.58 (m,4H), 1.17-0.88 (m, 7H). MS: m/z 437.3 (M+H⁺)

Example 163: Preparation of2-{4-cyclopropyl-2-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N-(2-hydroxy-ethyl)-N-methyl-acetamide

The title compound was prepared as described in example2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamide.¹H NMR (400 MHz, CDCl₃): δ=7.24-7.19 (m, 2H), 6.96 (t, J=7.6 Hz, 1H),6.91 (d, J=8.0 Hz, 1H), 4.93 (d, J=13.2 Hz, 2H), 3.89-3.77 (m, 7H), 3.66(t, J=4.8 Hz, 2H), 3.25-3.22 (m, 4H), 2.90 (t, J=12.6 Hz, 2H), 2.34 (s,3H), 1.90-1.63 (m, 5H), 1.17-1.15 (m, 2H), 0.94-0.89 (m, 2H). MS: m/z439.3 (M+H⁺)

Example 164: Preparation of2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N-methyl-N-propyl-acetamide

To a stirred solution of sodium (7.0 g, 304 mmol) in diethyl ether (400mL) was added Succinic acid ethyl ester methyl ester (50 g, 287 mmol)and formic acid ethyl ester (36.1 g, 488 mmol). The mixture was refluxedfor 5 h. After the cooling to room temperature. Water was added to themixture until the sodium sat was dissolved completely and aqueous layerwas separated. The aqueous layer was neutralizied by 6 M HCl and extratewith diethyl ether. The extracts were washed with sat. NaHCO₃, driedover anhydrous Na₂SO₄ and filtered. The filtrate was evaporated invacuum to residue, which was used directly next step without furtherpurification.

Thiourea (19.7 g, 259 mmol) and 2-formyl-succinic acid 4-ethyl ester1-methyl ester (56 g, 259 mmol) were added at room temperature to asolution of sodium (12 g, 518 mmol) in methanol (400 mL) and the mixturewas stirred under N₂ reflux for 18 h. After cooling, the precipitate wasfiltered off and added with stirring to a HCl (12 N) at 0° C. The whiteprecipitate was filtered, washed with water and dried to give of titlecompound (4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetic acid(25 g, yield: 35%) as a white power.

To a stirred solution of(4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetic acid (25 g,134.4 mmol) in methanol (300 mL) was added H₂SO₄ (15 mL). The mixturewas then heated to reflux overnight. The reaction was cooled to roomtemperature and was concentrated. The residue was washed with water andEA. and the solid was evaporated in vacuum to dryness to afford (13 g,yield: 52%) of (4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-aceticacid methyl ester as a white solid.

To a stirred solution of(4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-acetic acid methylester (13 g, 65 mmol) in POCl₃(100 mL). The mixture was then heated toreflux two days. The reaction was cooled to room temperature and wasconcentrated. and added into ice water (150 mL) dropwise. The aqueousmixture was neutralized with sat.NaHCO₃ to pH=8 and extracted with EA(200 mL×2). The combined organic layers were washed with brine (80 mL),dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated invacuum to residue, which was purified by silica gel chromatography (fromPE to PE/EA=5/1) to give (7.9 g, yield: 55%) of(2,4-dichloro-6-methyl-pyrimidin-5-yl)-acetic acid methyl ester asyellow solid.

To a stirred solution of (2,4-dichloro-6-methyl-pyrimidin-5-yl)-aceticacid methyl ester (1.2 g, 5.5 mmol) in ethanol (20 mL) was added DIEA(1.24 g, 10.9 mmol) and 4-(2-methoxy-phenyl)-piperidine (1.12 g, 4.9mmol). The mixture was stirred at room temperature for overnight. Themixture was evaporated in vacuum to residue, which was purified bysilica gel chromatography (PE/EA from 10/1 to 5/1) to give (1.0 g,yield: 40%) of{2-chloro-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester as yellow solid. MS Calculated 375.1, observed[M+H]=376.3.

To a mixture of{2-chloro-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester (800 mg, 2.1 mmol), cyclopropane boronic acid (542 mg,6.3 mmol) and K₃PO₄ (1.34 mg, 6.3 mmol) in THF (30 mL) was addedPd(dppf)Cl₂ (120 mg, 0.21 mmol). The mixture was stirred at 90° C. underN₂ for 18 h, cooled to room temperature and evaporated under reducedpressure to dryness. The residue was diluted with EA (200 mL) and washedwith water, dried over anhydrous Na₂SO₄, filtered. The filtrate wasevaporated in vacuum to residue, which was purified by silica gelchromatography (from PE to PE/EA=20/1) to give (180 mg, yield: 22.5%) of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.13 (s,1H), 7.24-7.22 (m, 2H), 6.98 (t, J=7.6 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H),3.95-3.88 (m, 5H), 3.76 (s, 3H), 3.59 (s, 2H), 3.26-3.18 (m, 1H), 3.04(t, J=12.0 Hz, 2H), 2.17-2.11 (m, 1H), 1.94-1.73 (m, 4H), 1.15-0.98 (m,4H). MS: m/z 382.3 (M+H⁺)

A mixture of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid methyl ester (180 mg, 0.47 mmol) in THF (10 mL), and LiOH in waterwas added dropwise. The reaction mixture was stirred at room temperaturefor overnight. The aqueous mixture was acid with HCl to pH=2. Thesuspension was filtered and the cake was washed with water (10 mL×2),then evaporated in vacuum to dryness to give (90 mg, yield: 52%) of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid as yellow solid.

To a stirred solution of{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-aceticacid (60 mg, 0.15 mmol) in DMF (2 mL) was added HATU (90 mg, 0.24 mmol)and Dimethyl-amine (0.15 mL, 0.3 mmol). The mixture was stirred at roomtemperature for overnight. The mixture was evaporated in vacuum toresidue, which was purified by pre-HPLC (MeCN/H₂O from 5/100 to 95/100)to give (30 mg, yield: 47%) of2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamideas white solid. ¹H NMR (400 MHz, CDCl₃): δ=8.08 (d, J=8.0 Hz, 1H),7.24-7.21 (m, 2H), 6.98-6.90 (m, 2H), 3.87-3.74 (m, 8H), 3.61-3.45 (m,3H), 3.32-3.16 (m, 1H), 3.14-2.96 (m, 5H), 2.14-2.11 (m, 1H), 1.91 (t,J=12.0 Hz, 2H), 1.78 (q, J=12.0 Hz, 2H), 1.12-0.97 (m, 4H). MS: m/z425.2 (M+H⁺).

Example 165: Preparation of2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrimidin-5-yl}-N-methyl-N-propyl-acetamide

The title compound was prepared as described for2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-N,N-dimethyl-acetamide.¹H NMR (400 MHz, CDCl₃): δ=8.14 (s, 1H), 7.24-7.20 (m, 2H), 6.98 (t,J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 3.88-3.84 (m, 5H), 3.89 (t, J=7.6Hz, 1H), 3.59 (d, J=8.4 Hz, 2H), 3.22-2.94 (m, 7H), 2.17-2.12 (m, 1H),1.96-1.91 (m, 2H), 1.84-1.77 (m, 2H), 1.61-1.51 (m, 2H). MS: m/z 423.3(M+H⁺).

Example 166: Preparation of2-({2-Cyclopropyl-8-fluoro-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: To a solution of 2-amino-3-fluorobenzoic acid (1.0 g, 6.45 mmol)in DMF (10 mL) at −10° C., NBS (1.15 g, 6.45 mmol) in DMF (4 mL) wasadded dropwise over 10 min. After the addition was complete, thereaction mixture was stirred at −10° C. for 1 h. The reaction wasquenched with aqueous sodium bisulfate (50 mL) and large amount of solidprecipitated out. The resulting solid was collected by filtration anddried in vacuum to afford 2-amino-5-bromo-3-fluorobenzoic acid (1.2 g,yield: 80%) as a yellow solid.

Step 2: To a solution of 2-amino-5-bromo-benzoic acid (1.2 g, 5.17 mmol)in pyridine (12 mL) was added cyclopropanecarbonyl chloride (807 mg,7.76 mmol). The reaction mixture was stirred at 60° C. overnight. Aftercooled to 0° C. at ice batch and poured into ice-water (100 mL), theresulting suspension was filtered and dried to give6-bromo-2-cyclopropyl-8-fluoro-4H-benzo[d][1,3]oxazin-4-one (751 mg,yield: 51%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ=8.12 (dd,J=9.6, 2.0 Hz, 1H), 7.98 (s, 1H), 2.08-1.95 (m, 1H), 1.20-1.10 (m, 4H).

Step 3: A suspension of6-bromo-2-cyclopropyl-8-fluoro-4H-benzo[d][1,3]oxazin-4-one (751 mg,2.64 mmol) in NH₃.H₂O (40 mL, 28%) was heated at 100° C. in a sealedtube overnight. After cooled to room temperature, the resulting solidwas filtered and the cake was washed with water, dried to give6-bromo-2-cyclopropyl-8-fluoroquinazolin-4-ol (521 mg, yield: 69%) as ayellow solid. MS: m/z 282.8 (M+H⁺).

Step 4: To a suspension of 6-bromo-2-cyclopropyl-8-fluoroquinazolin-4-ol(200 mg, 0.71 mmol), 4-(2-methoxy-phenyl)-piperidine hydrochloride (177mg, 0.78 mmol) and BOP (471 mg, 1.07 mmol) in ACN (20 mL) was added DBU(540 mg, 3.55 mmol). Then mixture was stirred at room temperatureovernight. The resulting solid was collected by filtration and dried invacuum to afford6-bromo-2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazoline(179 mg, yield: 55%) as a white solid. MS: m/z 455.8 (M+H⁺).

Step 5: To a solution of6-bromo-2-cyclopropyl-8-fluoro-4H-benzo[d][1,3]oxazin-4-one (179 mg,0.39 mmol) in anhydrous toluene (10 mL) was added BINAP (73 mg, 0.117mmol), Pd(OAc)₂ (13 mg, 0.059 mmol) and Cs₂CO₃ (254 mg, 0.78 mmol),purged with N₂ for 5 min, 2-(tert-butyl-dimethyl-silanyloxy)-ethylamine(138 mg, 0.79 mmol) was added. The mixture was stirred under N₂overnight. After cooled to room temperature, the mixture was filtered.The filtrate was concentrated to giveN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methylquinazolin-6-amine(375 mg crude) as a crude product, which was used to next step withoutfurther purification. MS: m/z 550.9 (M+H⁺).

Step 6: To a solution ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methylquinazolin-6-amine(crude, 375 mg, ˜0.39 mmol) in MeOH (30 mL) was added HCHO (0.6 mL, 40%in H₂O, 7.8 mmol), NaBH(ACO)₃ (827 mg, 3.9 mmol) and NaBH₃CN (246 mg,3.9 mmol). Then the reaction mixture was stirred at room temperatureovernight. The reaction was quenched with saturated aqueous NaHCO₃solution. The mixture was extracted with EA (30 mL×2). The organic layerwas washed with brine, dried over Na₂SO₄. The solution was concentratedto dryness and the residue (381 mg crude) was used to next step withoutfurther purification. MS: m/z 564.9 (M+H⁺).

Step 7: To a solution ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methylquinazolin-6-amine(crude, 381 mg, ˜0.39 mmol) in MeOH (20 mL) was added con. HCl (0.1 mL),the reaction mixture was stirred at room temperature overnight. NH₃.H₂Owas added to adjust pH to 7-8. The mixture was concentrated and theresidue was purified by prep-TLC (DCM/MeOH=20/1) to give24(2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol(20 mg, 3-step yield: 11%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃):δ=7.24-7.21 (m, 2H), 7.06 (dd, J=13.6, 2.4 Hz, 1H), 6.96 (t, J=8.0 Hz,1H), 6.89 (d, J=8.8 Hz, 1H), 6.71 (s, 1H), 4.36 (d, J=13.2 Hz, 2H),3.88-3.86 (m, 5H), 3.54-3.52 (m, 2H), 3.28-3.11 (m, 3H), 3.03 (s, 3H),2.27-2.25 (m, 1H), 1.98-1.86 (m, 4H), 1.16-1.14 (m, 2H), 0.99-0.96 (m,2H). MS: m/z 451.2 (M+H⁺).

Example 167: Preparation of2-({2-Cyclopropyl-5-fluoro-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described in example2-((2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.56-7.48 (m, 2H), 7.23-7.17 (m, 2H), 6.95(t, J=7.2 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.20 (d, J=12.4 Hz, 2H), 3.85(s, 3H), 3.74 (t, J=5.2 Hz, 2H), 3.25 (t, J=5.6 Hz, 2H), 3.10 (t, J=12.4Hz, 2H), 2.88 (s, 3H), 2.16-2.13 (m, 1H), 1.95-1.82 (m, 4H), 1.19-1.14(m, 2H), 1.00-0.95 (m, 2H). MS: m/z 451.2 (M+H⁺).

Example 168: Preparation of2-({2-Cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-5-yl}-methyl-amino)-ethanol

Step 1: To a solution of 2-amino-6-bromo-benzoic acid (2 g, 9.3 mmol) inpyridine (20 mL) was added cyclopropanecarbonyl chloride (1.25 mL, 13.9mmol). The reaction mixture was stirred at 60° C. overnight. Cooled to0° C., and poured into ice-water (100 mL), the resulting suspension wasfiltered and dried to give5-bromo-2-cyclopropyl-benzo[d][1,3]oxazin-4-one (1.75 g, yield: 71%) aswhite solid. ¹H NMR (300 MHz, CDCl₃): δ=7.68 (d, J=7.8 Hz, 1H), 7.53 (t,J=8.1 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 1.95-1.90 (m, 1H), 1.31-1.27 (m,2H), 1.16-1.11 (m, 2H).

Step 2: A suspension of 5-bromo-2-cyclopropyl-benzo[d][1,3]oxazin-4-one(1 g, 3.79 mmol) in NH₃H₂O (50 mL, 28%) was heated at reflux overnight.Cooled to rt, filtered, the cake was washed with water, dried to give5-bromo-2-cyclopropyl-quinazolin-4-ol (450 mg, 45% yield) as whitesolid. ¹H NMR (300 MHz, CDCl₃): δ=7.64-7.62 (m, 1H), 7.56-7.53 (m, 1H),7.50-7.47 (m, 1H), 1.84-1.82 (m, 1H), 1.32-1.28 (m, 2H), 1.17-1.13 (m,2H).

Step 3: To a suspension of 5-bromo-2-cyclopropyl-quinazolin-4-ol (215mg, 0.81 mmol), L-proline (47 mg, 0.41 mmol), CuI (46 mg, 0.24 mmol) andK₂CO₃ (224 mg, 1.62 mmol) in DMSO (4 mL) was added2-(methylamino)ethanol (91 mg, 1.22 mmol) after purged with N₂ for 5min. Then the mixture was heated to 90° C. and it was stirred at asealed tube overnight. After cooled to room temperature, the reactantwas filtered. The filtrate was concentrated to dryness and the residuewas purified by prep-HPLC (NH₄HCO₃ as additive) to afford2-cyclopropyl-5-((2-hydroxyethyl)(methyl)amino)quinazolin-4-ol (50 mg,yield: 23%) as brown oil. ¹H NMR (400 MHz, CDCl₃): δ=10.73 (brs, 1H),7.55 (t, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H),4.40 (brs, 1H), 3.76-3.72 (m, 2H), 3.35-3.30 (m, 2H), 2.87 (s, 3H),1.93-1.87 (m, 1H), 1.30-1.20 (m, 2H), 1.13-1.08 (m, 2H). MS: m/z 260.0(M+H⁺)

Step 4: To a solution of2-cyclopropyl-5-((2-hydroxyethyl)(methyl)amino)quinazolin-4-ol (25 mg,0.097 mmol) in DCM (5 mL) was added TBSCl (16 mg, 0.106 mmol) and TEA(19.6 mg, 0.194 mmol), and the mixture was stirred at room temperaturefor 2 h. But LC-MS showed no reaction. So the mixture was concentratedto dryness and the residue was dissolved in MeCN (5 mL), followed by theaddition of K₂CO₃ (27 mg, 0.194 mmol, 2 eq.) and TBSCl (16 mg, 0.106mmol, 1.1 eq). The mixture was stirred at 60° C. for 4 h. LC-MS showedthe reaction was completed. The reaction was quenched by water (10 mL).The aqueous phase was extracted with DCM (20 mL×3). The extracts werewashed with brine (20 mL×2) and dried over Na₂SO₄. The solution wasconcentrated to dryness and the residue (40.6 mg, yield: >100%) was usedfor next step without further purification. ¹H NMR (400 MHz, CDCl₃):δ=10.55 (brs, 1H), 7.55-7.50 (m, 1H), 7.13-7.08 (m, 1H), 6.95-6.91 (m,1H), 3.84 (t, J=6.0 Hz, 2H), 3.41 (t, J=6.0 Hz, 2H), 3.03 (s, 3H),1.92-1.85 (m, 1H), 1.30-1.25 (m, 2H), 1.13-1.06 (m, 2H), 0.85 (s, 9H),0.01 (s, 6H).

Step 5: To a suspension of5-(2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-2-cyclopropylquinazolin-4-ol(40 mg, 0.11 mmol), 4-(2-methoxy-phenyl)-piperidine hydrochloride (26.7mg, 0.12 mmol) and BOP (73 mg, 0.17 mmol) in ACN (10 mL) was added DBU(84 mg, 0.55 mmol). Then mixture was stirred at room temperatureovernight. The reaction was quenched with water (10 mL) and the aqueousphase was extracted with EtOAc (20 mL×3). The extracts were dried overNa2SO4 and the solution was concentrated to dryness. The crude wassubmitted for next step without further purification. MS: m/z 547.0(M+H⁺).

Step 6: To a solution ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methylquinazolin-5-amine(crude, 100 mg, ˜0.11 mmol) in MeOH (10 mL) was added con. HCl (0.1 mL),the reaction mixture was stirred at room temperature overnight. NH₃.H₂O(0.1 mL) was added to adjust pH to 7˜8. The mixture was concentrated andthe residue was purified by prep-TLC (DCM/MeOH=20/1) to give2-((2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol(14 mg, 3-step yield: 33%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃):δ=7.60 (d, J=8.0 Hz, 1H), 7.30-7.28 (m, 1H), 7.06-6.86 (m, 3H), 3.83 (s,3H), 3.80-3.63 (m, 2H), 3.55-3.21 (m, 5H), 3.00-2.97 (m, 2H), 2.65 (d,J=9.6 Hz, 3H), 2.29-2.27 (m, 2H), 2.04-1.89 (m, 7H). MS: m/z 433.2(M+H⁺).

Example 169: Preparation of2-({2-Cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-7-yl}-methyl-amino)-ethanol

The title compound was prepared as described in example2-({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-5-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.67 (d, J=9.6 Hz, 1H), 7.22-7.19 (m, 2H),6.97-6.88 (m, 4H), 4.37 (d, J=12.4 Hz, 2H), 3.88-3.85 (m, 5H), 3.63-3.62(m, 2H), 3.29-3.23 (m, 1H), 3.18-3.11 (m, 5H), 2.13-2.12 (m, 1H),1.90-1.82 (m, 5H), 1.16 (m, 2H), 0.95-0.93 (m, 2H). MS: m/z 433.2(M+H⁺).

Example 170: Preparation of{2-Cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-7-yl}-methyl-propyl-amine

The title compound was prepared as described in example2-({2-Cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-5-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.63 (d, J=9.3 Hz, 1H), 7.28-7.15 (m, 3H),6.97-6.89 (m, 2H), 6.83 (dd, J=9.0, 1.2 Hz, 1H), 4.67 (d, J=12.0 Hz,2H), 3.87 (s, 3H), 3.47-3.31 (m, 5H), 3.11 (s, 3H), 2.50-2.40 (m, 1H),2.05-1.98 (m, 2H), 1.92-1.62 (m, 4H), 1.27-1.13 (m, 4H), 0.97 (t, J=7.2Hz, 3H). MS: m/z 431.3 (M+H⁺).

Example 171: Preparation of(1-Fluoro-cyclopropyl)-{7-fluoro-6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-2-yl}-methanone

The title compound was prepared as described in example2-((2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol.¹H NMR (400 MHz, CD₃OD): δ=7.50 (d, J=14.4 Hz, 1H), 7.34 (d, J=9.6 Hz,1H), 7.23-7.18 (m, 2H), 6.98-6.93 (m, 2H), 4.46-4.43 (m, 2H), 3.86-3.79(m, 6H), 3.45-3.42 (m, 2H), 3.27-3.21 (m, 2H), 3.06 (s, 3H), 1.96-1.93(m, 4H), 1.55- 1.48 (m, 4H). MS: m/z 469.2 (M+H⁺).

Example 172: Preparation of{7-Chloro-6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-2-yl}-(1-fluoro-cyclopropyl)-methanone

The title compound was prepared as described in example2-((2-cyclopropyl-8-fluoro-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol.¹H NMR (400 MHz, CD₃OD): δ=7.97 (s, 1H), 7.75 (s, 1H), 7.25-7.21 (m,2H), 7.00-6.91 (m, 2H), 4.96-4.93 (m, 2H), 3.87 (s, 3H), 3.83 (t, J=5.6Hz, 2H), 3.64-3.51 (m, 3H), 3.40 (t, J=5.6 Hz, 2H), 3.04 (s, 3H),2.14-2.11 (m, 2H), 1.98-1.74 (m, 6H). MS: m/z 485.2 (M+H⁺).

Example 173: Preparation of(S)-1-(2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)pyrrolidin-3-oland Example 174: Preparation of(S)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline

Step 1: To a mixture of (S)-pyrrolidin-3-ol (494 mg, 5.69 mmol) in DCM(15 mL) was added imidazole (772 mg, 11.37 mmol) and TBSCl (1.03 g, 6.81mmol), cooled to 0° C. under N₂ atmosphere. The resulting mixture wasstirred for overnight at room temperature. The mixture was partitionedbetween NaHCO₃ (sat. 50 mL) and DCM (50 mL). The aqueous phase wasextracted with DCM (50 mL×2). The combined organic layer was washed withwater (100 mL×2), dried over Na₂SO₄ and concentrated to give(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine (576 mg, crude) as ayellow oil. ¹H NMR (400 MHz, CDCl₃): 4.30-4.27 (m, 1H), 3.08-3.02 (m,1H), 2.80-2.74 (m, 3H), 1.84-1.77 (m, 1H), 1.64-1.59 (m, 1H), 0.82 (s,9H), 0.00 (s, 6H),

Step 2: To a mixture of6-bromo-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(438 mg, 1.00 mmol), (S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine(402 mg, 2.00 mmol) and Cs₂CO₃ (652 mg, 2.00 mmol) in anhydrous toluene(40 mL), BINAP (125 mg, 0.20 mmol) and Pd(OAc)₂ (5.0 mg, 0.024 mmol),and the mixture was stirred at at 90° C. overnight under N₂ atmosphere.The suspension was concentrated under reduced pressure. The residue waspartitioned between water (80 mL) and EtOAc (80 mL). The aqueous phasewas extracted with EtOAc (60 mL×2). The extracts were washed with water(100 mL×2) and brine (100 mL×1), then dried over Na₂SO₄. The solutionwas concentrated to dryness and the residue was purified by silica gelcolumn chromatography (PE/EA=3/1) to give(S)-6-[3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(470 mg, yield: 84%) as a yellow solid. MS: m/z 559.1 (M+H⁺)

Step 3: To a solution of(S)-6-[3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazoline(470 mg, 0.84 mmol) in MeOH (20 mL) was added conc.HCl (four drops), andthe reaction mixture was stirred at room temperature for overnight. Themixture was concentrated under reduced pressure. The residue waspartitioned between NaHCO₃ (sat. 40 mL) and EtOAc (40 mL). The aqueousphase was extracted with EtOAc (40 mL×2). The combined organic layerswere washed with water (100 mL×2) and brine (100 mL×1), and dried overNa₂SO₄. The solution was concentrated to dryness and the residue waspurified by silica gel column chromatography (DCM/MeOH=30/1),lyophilized to afford(S)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol(370 mg, yield: 99%) as a white solid. ¹H NMR (400 HMz, CD₃OD): δ=7.51(dd, J=7.2, 1.2 Hz, 1H), 7.48 (dd, J=7.2, 2.4 Hz, 1H), 7.13-7.07 (m,2H), 6.86 (d, J=8.0 Hz, 1H), 6.83-6.78 (m, 1H), 6.76 (d, J=2.4 Hz, 1H),4.90-4.87 (m, 2H), 4.49-4.48 (m, 1H), 3.75 (s, 3H), 3.52-3.37 (m, 6H),3.23-3.22 (m, 1H), 2.16-2.06 (m, 1H), 2.03-1.96 (m, 4H) 1.85- 1.75 (m,2H), 1.26-1.15 (m, 4H). MS: m/z 445.2 (M+H⁺)

Step 4: To a solution of(S)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol(150 mg, 0.34 mmol) in anhydrous THF (20 mL) was added NaH (60%, 54 mg,1.35 mmol), and the mixture was stirred for 1 h at room temperature.Then (CH₃)₂SO₄ (42 mg, 0.34 mmol) was added into the mixture. Thereaction mixture was stirred at room temperature for overnight. Themixture was concentrated under reduced pressure. The residue waspartitioned between water (50 mL) and EtOAc (50 mL). The aqueous phasewas extracted with EtOAc (50 mL×2). The organic layer was washed withwater (80 mL×2) and brine (80 mL×1), dried over Na₂SO₄. The solution wasconcentrated to dryness and the residue was purified by Pre-TLC(DCM/MeOH=10/1) and lyophilized to give(S)-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)-quinazoline(66 mg, yield: 42%) as a yellow solid. ¹H NMR (400 HMz, CD₃OD): δ=7.49(d, J=9.2 Hz, 1H), 7.26 (dd, J=9.2, 2.4 Hz, 1H), 7.12-7.07 (m, 2H), 6.86(d, J=8.4 Hz, 1H), 6.81 (t, J=8.4 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H),4.88-4.85 (m, 2H), 4.10-4.09 (m, 1H), 3.75 (s, 3H), 3.51-3.31 (m, 7H),3.28 (s, 3H), 2.16-1.95 (m, 5H), 1.81-1.77 (m, 2H), 1.24-1.15 (m, 4H).MS: m/z 459.2 (M+H⁺).

Example 175: Preparation of(R)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol

The title compound was prepared using general procedure for(S)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol.¹H NMR (400 HMz, CD₃OD): δ=7.62 (d, J=8.8 Hz, 1H), 7.42-7.39 (m, 1H),7.24-7.20 (m, 2H), 7.00-6.90 (m, 3H), 5.03-5.00 (m, 2H), 4.62-4.60 (m,1H), 3.88 (s, 3H), 3.52-3.37 (m, 6H), 3.60-3.51 (m, 6H), 2.26-2.23 (m,1H), 2.18-2.09 (m, 4H) 1.97-1.91 (m, 2H), 1.37-1.29 (m, 4H). MS: m/z445.2 (M+H⁺).

Example 176: Preparation of(R)-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)-quinazoline

The title compound was prepared using general procedure for(S)-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)-quinazoline.¹H NMR (400 HMz, CD₃OD): δ=7.52 (d, J=8.8 Hz, 1H), 7.18-7.06 (m, 3H),6.86-6.80 (m, 2H), 6.65 (d, J=2.4 Hz, 1H), 4.38-4.34 (m, 2H), 4.09-4.08(m, 1H), 3.75 (s, 3H), 3.50-3.46 (m, 1H), 3.37-3.29 (m, 4H), 3.28 (s,3H), 3.11-3.04 (m, 2H), 2.12-1.97 (m, 3H), 1.84-1.79 (m, 2H), 1.06-1.03(m, 2H), 0.90-0.86 (m, 4H). MS: m/z 459.2 (M+H⁺).

Example 177: Preparation of(S)-1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol

The title compound was prepared using general procedure for(S)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol.¹H NMR (400 HMz, CDCl₃): δ=7.91 (d, J=9.2 Hz, 1H), 7.26-7.16 (m, 3H),6.99-6.95 (m, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H),4.68-4.66 (m, 1H), 4.38-4.35 (m, 2H), 3.86 (s, 3H), 3.63-3.60 (m, 2H),3.47-3.45 (m, 1H), 3.38- 3.36 (m, 1H), 3.29-3.27 (m, 1H), 3.15-3.09 (m,2H), 2.26-2.21 (m, 1H) 2.15-2.13 (m, 1H), 1.98-1.87 (m, 4H), 0.89-0.83(m, 4H). MS: m/z 463.2 (M+H⁺)

Example 178: Preparation of(R)-1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol

The title compound was prepared using general procedure for(S)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol.¹H NMR (400 HMz, CDCl₃): δ=7.90 (d, J=9.2 Hz, 1H), 7.26-7.16 (m, 3H),6.96 (t, J=7.6 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H),4.68-4.66 (m, 1H), 4.38-4.35 (m, 2H), 3.86 (s, 3H), 3.63-3.60 (m, 2H),3.47-3.45 (m, 1H), 3.38-3.36 (m, 1H), 3.29-3.27 (m, 1H), 3.15-3.09 (m,2H), 2.45-2.21 (m, 1H) 2.14-2.13 (m, 1H), 1.98-1.87 (m, 4H), 0.89-0.83(m, 4H). MS: m/z 463.2 (M+H⁺)

Example 179: Preparation of({2-Cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-aceticacid

To a solution of2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-amine(200 mg, 0.534 mmol) in MeOH (30 mL) was added ethyl 2-oxoacetate (470mg, 5.34 mmol), followed by NaBH₃CN (1.13 g, 5.34 mmol) and NaBH(OAc)₃(0.335 g, 5.34 mmol), and the resulting mixture was stirred at roomtemperature for overnight. Then to the reaction mixture was added HCHO(37-40%, 1.0 mL), and the reaction was stirred for overnight. Thereaction mixture was concentrated to dryness in vacuum. The residue wasdiluted with ice-water (100 mL), and the mixture was extracted withEtOAc (100 mL×2). The combined organic layers were dried over Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby Prep-HPLC to afford({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-aceticacid (35 mg, yield: 21%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6):δ=8.02-8.00 (m, 1H), 7.27-7.20 (m, 1H), 7.15-7.09 (m, 2H), 6.96-6.82 (m,3H), 4.85-4.82 (m, 2H), 4.16 (s, 2H), 3.85 (s, 3H), 3.43-3.35 (m, 3H),3.10 (s, 3H), 2.72-2.69 (m, 1H), 2.08-2.04 (m, 2H), 1.84-1.77 (m, 2H),1.30-1.15 (m, 4H). MS: m/z 447.2 (M+H⁺).

Example 180: Preparation of2-((2-(1-fluorocyclopropyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)aceticacid

The title compound was prepared using general procedure for({2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-aceticacid as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ=7.64-7.60 (m, 1H),7.19-7.06 (m, 3H), 6.88-6.76 (m, 3H), 4.34-4.28 (m, 2H), 4.05-4.03 (m,1H), 3.78-3.76 (m, 1H), 3.75 (s, 3H), 3.15-2.95 (m, 6H), 2.00-1.39 (m,8H). MS: m/z 465.2 (M+H⁺).

Example 181: Preparation of2-((8-chloro-2-(1-fluorocyclobutyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol

Step 1: To a solution of ethyl cyclobutanecarboxylate (38.4 g, 0.3 mol)and HMPA (80.5 g, 0.45 mol) in anhydrous THF (500 mL) was added LDA (2M,225 mL) dropwise at −78° C. After addition, the mixture was stirred atthis temperature for 25 min.N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (113.4 g, 0.36 mol) wasadded thereto at −78° C. Then the solution was allowed to warm to roomtemperature and stirred overnight. The reaction solution wasconcentrated till one third of the volume was kept. The remainingsolution was diluted with EtOAc (500 mL). The mixture was washed with 1NHCl (300 mL), sodium bicarbonate solution (300 mL), brine (300 mL×2) anddried over Na₂SO₄. The solvent was removed to give a crude product (107g crude) as brown oil.

Step 2: To a solution of the crude ethyl 1-fluorocyclobutanecarboxylate(103 g crude) in EtOH (500 mL) was added aqueous KOH (100 mL water,16.24 g, 0.29 mol). The mixture was stirred at room temperature for 6 h.The solution was concentrated to remove most of MeOH. The remainingsolution was diluted with EtOAc (500 mL) and extracted with water (300mL×2). The aqueous layer was acidified with HCl to pH=1-2 and thenextracted with EtOAc (500 mL×2). The extracts were dried over Na₂SO₄ andconcentrated to give crude 1-fluorocyclobutanecarboxylic acid (8.2 g) asbrown oil. ¹H NMR (400 MHz, CDCl₃): δ=2.53-2.48 (m, 2H), 2.35-2.20 (m,2H), 2.10-1.92 (m, 2H).

Step 3: To a solution of 2-amino-3-chlorobenzonitrile (2 g, 13.1 mmol)in DMF (50 mL) was added NBS (2.4 g, 14.4 mmol), and the mixture wasstirred at room temperature overnight. The reaction was quenced withwater (100 mL). The mixture was extracted with EtOAc (100 mL×3). Theextracts were concentrated to dryness and the residue was purified bycombi flash (EtOAc/PE=0/1-3/7) to afford2-amino-5-bromo-3-chlorobenzonitrile (1.8 g, yield: 58%) as a whitesolid.

Path 1 to 6-bromo-8-chloro-2-(1-fluorocyclobutyl)quinazolin-4-ol

Step 4, 5: To a solution of 1-fluorocyclobutanecarboxylic acid (300 mgcrude) in anhydrous DCM (6 mL) was added oxalyl chloride (0.2 mL, 2.5mmol) and 2 drops of DMF at 0° C., and the mixture was stirred at roomtemperature for 2 h. To another flash containing a solution of2-amino-5-bromo-3-chlorobenzonitrile (520 mg, 2.25 mmol) in pyridine (3mL) was added the above acyl chloride. The reaction mixture was stirredat reflux overnight. LCMS observed the desired mass value (330.7). Thereaction was diluted with DCM (20 mL) and washed with 1N HCl (10 mL) andbrine (20 mL). The organic layer was dried over Na₂SO₄ and concentratedto dryness. The residue was purified by prep-HPLC to affordN-(4-bromo-2-chloro-6-cyanophenyl)-1-fluorocyclobutanecarboxamide (43mg, yield: 5.8%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=7.92(brs, 1H), 7.78 (s, J=1.0 Hz), 7.68 (s, J=2.4 Hz), 2.78-2.68 (m, 2H),2.54-2.38 (m, 2H), 2.00-1.54 (m, 2H). MS: m/z 330.7 (M+H⁺).

To a solution ofN-(4-bromo-2-chloro-6-cyanophenyl)-1-fluorocyclobutanecarboxamide (174mg, 0.53 mmol) in EtOH (10 mL) was added H₂O₂ (1 mL) and NaOH (21 mg,0.53 mmol), and the mixture was stirred at 90° C. for 2 h. LCMS showedthe reaction was fine. The reaction was concentrated and the residue waswashed with water (3 mL). The resulting solid was collected byfiltration to afford6-bromo-8-chloro-2-(1-fluorocyclobutyl)quinazolin-4-ol (136 mg, yield:28%) as a white solid. MS: m/z 330.7 (M+H⁺).

Path 2 to 6-bromo-8-chloro-2-(1-fluorocyclobutyl)quinazolin-4-ol

Step 4, 5, 6: To a solution of 2-amino-5-bromo-3-chlorobenzonitrile (2g, 8.6 mmol) in the mixture solvent MeOH (2 mL), water (10 mL) and H₂O₂(2 mL) was added NaOH (688 mg, 17.2 mmol), and the mixture was stirredat room temperature overnight. The resulting solid was collected byfiltration to afford 2-amino-5-bromo-3-chlorobenzamide (2.3 g, >100%crude yield) as a white solid.

To a solution of 1-fluorocyclobutanecarboxylic acid (236 mg crude) inanhydrous DCM (4 mL) was added oxalyl chloride (254 mg, 2 mmol) and 2drops of DMF at 0° C., and the mixture was stirred at room temperaturefor 2 h. To another flash containing a solution of2-amino-5-bromo-3-chlorobenzamide (250 mg, 1 mmol) in pyridine (2 mL)was added the above acyl chloride. The reaction mixture was stirred atreflux overnight. LCMS observed the desired mass value (348.7). Thereaction was diluted with DCM (20 mL) and washed with 1N HCl (10 mL) andbrine (20 mL). The organic layer was dried over Na₂SO₄ and concentratedto dryness. The residue was purified by prep-TLC to afford5-bromo-3-chloro-2-(1-fluorocyclobutanecarboxamido)benzamide (30 mg,yield: 8.6%) as a yellow solid. MS: m/z 348.7 (M+H⁺). ¹H NMR (400 MHz,CDCl₃): δ=8.50 (brs, 1H), 7.68 (d, J=2.0 Hz), 7.61 (d, J=2.4 Hz), 6.41(brs, 1H), 6.02 (brs, 1H), 2.75-2.67 (m, 2H), 2.68-2.41 (m, 2H),2.11-1.90 (m, 2H).

To a solution of5-bromo-3-chloro-2-(1-fluorocyclobutanecarboxamido)benzamide (30 mg,0.086 mmol) in t-BuOH (10 mL) was added t-BuOK (11.6 mg, 0.103 mmol),and the mixture was stirred at reflux for 1.5 h. LCMS showed thereaction was fine. The reaction was concentrated and the residue (40 mgcrude) as a yellow solid was used for next step without furtherpurification. MS: m/z 330.7 (M+H⁺).

Step 7: To a suspension of8-chloro-2-(1-fluorocyclobutyl)-6-((2-hydroxyethyl)(methyl)amino)quinazolin-4-ol(35 mg, 0.11 mmol), 4-(2-methoxy-phenyl)-piperidine hydrochloride (30mg, 0.13 mmol) and BOP (75 mg, 0.17 mmol) in ACN (10 mL) was added DBU(50 mg, 0.33 mmol). Then mixture was stirred at room temperatureovernight. The reactant was concentrated to dryness and the residue waspurified by prep-HPLC to afford2-((8-chloro-2-(1-fluorocyclobutyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol(11 mg, yield: 20%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=7.89(d, J=9.3 Hz, 1H), 7.24-7.20 (m, 2H), 6.98-6.89 (m, 3H), 4.43 (d, J=12.4Hz, 2H), 3.88 (s, 3H), 3.72-3.70 (m, 4H), 3.63-3.58 (m, 2H), 3.34-3.18(m, 3H), 3.08 (s, 3H), 2.90-2.88 (m, 2H), 2.67-2.62 (m, 2H), 2.01-1.96(m, 6H). MS: m/z 499.2 (M+H⁺).

Example 182: Preparation of3-{8-Chloro-2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-cyclopentanol

The title compound was prepared using general procedure for2-((8-chloro-2-(1-fluorocyclobutyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.28-7.21 (m, 3H), 6.99-6.89 (m, 2H), 6.68(s, 1H), 4.68 (brs, 1H), 4.43 (d, J=12.4 Hz, 2H), 3.88 (s, 3H),3.62-3.56 (m, 2H), 3.46-3.18 (m, 5H), 3.94-2.70 (m, 2H), 2.67-2.62 (m,2H), 2.24-2.13 (m, 2H), 2.02-1.78 (m, 7H). MS: m/z 511.2 (M+H⁺).

Example 183: Preparation of3-{8-Chloro-2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-cyclopentanol

The title compound was prepared using general procedure for2-((8-chloro-2-(1-fluorocyclobutyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol.NMR (400 MHz, CDCl₃): δ=7.26-7.16 (m, 3H), 6.91-6.81 (m, 2H), 6.62 (s,1H), 4.62 (brs, 1H), 4.40 (d, J=12.4 Hz, 2H), 3.79 (s, 3H), 3.56-3.50(m, 2H), 3.40-3.18 (m, 5H), 2.87-2.82 (m, 2H), 2.63-2.56 (m, 2H),2.15-2.05 (m, 2H), 1.93-1.79 (m, 7H). MS: m/z 511.2 (M+H⁺).

Example 184: Preparation of2-({2-Cyclopropyl-4-[4-(2-methoxy-cyclopentyl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: To a mixture of 6-oxa-bicyclo[3.1.0]hexane (5 mL) andpiperazine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) was addedZrCl₄ (246 mg, 1.07 mmol) and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with water (200mL). The aqueous layer was extracted with EtOAc (100 mL×3). The extractswere dried over Na₂SO₄. The mixture was filtered and the solvent removedby evaporation under reduced pressure to give 2-amino-6-chloro-benzoicacid methyl ester (1.7 g, yield: 58%) as a colorless oil, which was usedfor next step without further purification.

Step 2: To a solution of tert-butyl4-(2-hydroxycyclopentyl)piperazine-1-carboxylate (1.7 g, 6.29 mmol) inDMF (10 mL) at room temperature, was added NaH (310 mg, 7.6 mmol). Afterthe addition was complete, the reaction mixture was stirred at roomtemperature for 0.5 h before CH₃I (981 mg, 6.29 mmol). The reaction wasstirred at room temperature overnight and then quenched with water (150mL). The aqueous layer was extracted with EtOAc (100 mL×2). The organiclayers were washed with brine (100 mL×2) and dried over Na₂SO₄. Thesolution was concentrated and purified by silica gel column(PE/EA=50/1-10/1) to afford tert-butyl4-(2-methoxycyclopentyl)piperazine-1-carboxylate (1.2 g, yield: 67%) asa colorless oil.

Step 3: To a solution of tert-butyl4-(2-methoxycyclopentyl)piperazine-1-carboxylate (1.2 g, 4.2 mmol) inHCl/dioxane (10 mL) was stirred at room temperature overnight. The solidwas filtered and dried to give 1-(2-methoxycyclopentyl)piperazine HClsalt (1.4 g, yield: >100%) as white solid.

Step 4: To a mixture of2-cyclopropyl-6-((2-hydroxyethyl)(methyl)amino)quinazolin-4-ol (100 mg,0.39 mmol) and 1-(2-methoxycyclopentyl)piperazine (128 mg, 0.58 mmol) inMeCN (20 mL) was added DBU (178 mg, 1.17 mmol) and BOP (165 mg, 0.57mmol). Reaction mixture was stirred at room temperature overnight.Resultant was concentrated and purified by pre-HPLC to afford2-((2-cyclopropyl-4-(4-(2-methoxycyclopentyl)piperazin-1-yl)quinazolin-6-yl)(methyl)amino)ethan-1-ol(35 mg, yield: 21%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ=7.56(d, J=9.2 Hz, 1H), 7.43 (dd, J=9.6, 2.8 Hz, 1H), 6.75 (d, J=1.6 Hz, 1H),4.76-4.74 (m, 1H), 3.73-3.47 (m, 8H), 3.48-3.34 (m, 4H), 3.21 (s, 3H),3.01 (s, 3H), 2.71-2.68 (m, 4H), 2.07-2.03 (m, 1H), 1.86-1.75 (m, 2H),1.60-1.49 (m, 4H), 0.99- 0.90 (m, 4H). MS: m/z 426.1 (M+H⁺).

Example 185: Preparation of2-cyclopropyl-4-(4-(2-methoxycyclopentyl)piperazin-1-yl)-N-methyl-N-propylquinazolin-6-amine

The title compound was prepared as described in example2-{[8-fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol.¹H NMR (400 MHz, DMSO-d6): δ=7.56 (d, J=9.3 Hz, 1H), 7.43 (dd, J=9.3,2.7 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 3.68-3.63 (m, 1H), 3.53-3.43 (m,4H), 3.38-3.30 (m, 2H), 3.20 (s, 3H), 2.98 (s, 3H), 2.71-2.52 (m, 5H),2.07-1.97 (m, 1H), 1.83-1.05 (m, 8H), 1.00-0.85 (m, 7H). MS: m/z 424.4(M+H⁺).

Example 186: Preparation of2-({2-Cyclopropyl-4-[1-(2-methoxy-phenyl)-pyrrolidin-3-ylamino]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: To a solution of 2-bromo anisole (1.2 g, 6.45 mmol) in degassedtoluene (20 mL) was added a suspension of Pd₂(dba)₂ (494 mg, 0.54 mmol),BINAP (1 g, 1.61 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (1 g,5.37 mmol), and the mixture was stirred at 100° C. for 16.5 h underargon. The reactant was portioned between water (30 mL) and EtOAc (20mL). The organic layer was separated and the aqueous phase was extractedwith EtOAc (20 mL×2). The combined organic layers were washed with brine(10 mL×2) and concentrated to dryness. The crude product was purified byCombi flash (PE/EtOAc=50/1-20/1) to give tert-butyl(1-(2-methoxyphenyl)pyrrolidin-3-yl)carbamate (1.43 g, yield: 91%) asyellow oil.

¹H NMR (400 MHz, CDCl₃): δ=6.91-6.84 (m, 4H), 6.73 (d, J=6.4 Hz, 1H),4.85 (brs, 1H), 4.30 (brs, 1H), 3.83 (s, 3H), 3.55-3.44 (m, 2H),3.25-3.15 (m, 2H), 2.31-2.23 (m, 1H), 1.85-1.79 (m, 1H), 1.45 (s, 9H).

Step 2: To a solution of tert-butyl(1-(2-methoxyphenyl)pyrrolidin-3-yl)carbamate (460 mg, 2.4 mmol) inEtOAc (10 mL) was added HCl/dioxane (10 mL), and the mixture was stirredat room temperature overnight. The resulting solid was filtered and thecake was dissolved in MeOH. The solution was concentrated in vacuum togive 1-(2-methoxyphenyl)pyrrolidin-3-amine (294 mg, yield: 70%) as HClsalt and brown oil. ¹H NMR (400 MHz, DMSO-d6): δ=8.72 (brs, 3H),7.38-7.36 (m, 1H), 7.22-7.13 (m, 1H), 7.00 (t, J=7.6 Hz, 1H), (brs, 1H),3.98-3.96 (m, 1H), 3.88 (s, 3H), 3.81-3.48 (m, 4H), 2.45-2.40 (m, 1H),2.21-2.16 (m, 1H).

Step 3: To a suspension of2-cyclopropyl-6-((2-hydroxyethyl)(methyl)amino)quinazolin-4-ol (50 mg,0.19 mmol), 1-(2-methoxyphenyl)pyrrolidin-3-amine hydrochloride (56 mg,0.21 mmol) and BOP (126 mg, 0.29 mmol) in ACN (10 mL) was added DBU (144mg, 0.95 mmol). Then mixture was stirred at room temperature forweekend. The reaction was quenched with water (10 mL) and the aqueousphase was extracted with EtOAc (20 mL×3). The extracts were dried overNa₂SO₄ and the solution was concentrated to dryness. The crude waspurified by prep-TLC (DCM/MeOH=30/1) and prep-HPLC to afford2-({2-Cyclopropyl-4-[1-(2-methoxy-phenyl)-pyrrolidin-3-ylamino]-quinazolin-6-yl}-methyl-amino)-ethanol(6.3 mg, yield: 7%) as yellow solid. ¹H NMR (CDCl₃, 400 HMz): 6=7.58 (d,J=9.2 Hz, 1H), 7.20-7.17 (m, 1H), 6.92-6.87 (m, 3H), 6.82-6.79 (m, 2H),6.32 (brs, 1H), 4.91 (d, J=6.8 Hz, 1H), 3.85-3.82 (m, 5H), 3.63-3.52 (m,4H), 3.45-3.42 (m, 1H), 3.27-3.24 (m, 1H), 3.00 (s, 3H), 2.47-2.44 (m,2H), 2.18-2.09 (m, 3H), 1.15 (m, 2H), 0.97-0.94 (m, 2H). MS: m/z 434.2(M+H⁺).

Example 187: Preparation of2-Cyclopropyl-N4-[1-(2-methoxy-phenyl)-pyrrolidin-3-yl]-N6-methyl-N6-propyl-quinazoline-4,6-diamine

The title compound was prepared as described in example2-({2-cyclopropyl-4-[1-(2-methoxy-phenyl)-pyrrolidin-3-ylamino]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 HMz, CDCl₃): δ=7.81-7.78 (m, 1H), 7.29-7.26 (m, 1H),6.94-6.89 (m, 3H), 6.84-6.82 (m, 1H), 6.49 (m, 1H), 4.93 (d, J=11.2 Hz,1H), 3.87 (s, 3H), 3.61-3.56 (m, 2H), 3.49-3.48 (m, 1H), 3.36 (t, J=7.6Hz, 2H), 3.27-3.24 (m, 1H), 3.01 (s, 3H), 2.50-2.47 (m, 1H), 2.08-2.04(m, 1H), 1.67-1.59 (m, 3H), 1.26-1.16 (m, 2H), 1.05- 0.92 (m, 5H). MS:m/z 432.2 (M+H⁺).

Example 188: Preparation of2-{[4-(4-Cyclohexyl-piperidin-1-yl)-2-(1-fluoro-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described in example2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹HNMR (400 MHz, CDCl₃): δ=7.89 (d, J=9.2 Hz, 1H), 7.40-7.37 (m, 1H),6.92 (s, 1H), 4.25 (d, J=12.8 Hz, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.57 (t,J=6.0 Hz, 2H), 3.07 (s, 3H), 2.96-2.90 (m, 2H), 1.82-1.75 (m, 7H),1.51-1.39 (m, 6H), 1.25-1.16 (m, 5H), 0.99-0.96 (m, 2H). MS: m/z 427.3(M+H⁺).

Example 189: Preparation of2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-cyclohexyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described in example2-({2-cyclopropyl-4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.89 (d, J=8.8 Hz, 1H), 7.41-7.37 (m, 1H),6.93 (s, 1H), 4.25 (d, J=13.6 Hz, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.57 (t,J=5.6 Hz, 2H), 3.52 (s, 1H), 3.30 (s, 3H), 3.07 (s, 3H), 3.02-2.93 (m,2H), 2.12 (d, J=14.8 Hz, 1H), 1.92 (t, J=14.0 Hz, 2H), 1.76 (d, J=14.4Hz, 2H), 1.49-1.42 (m, 6H), 1.34-1.24 (m, 5H), 1.19-1.14 (m, 2H). MS:m/z 457.3 (M+H⁺).

Example 190: Preparation of2-({2-Cyclopropyl-4-[4-(3-methoxy-thiophen-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (50 g,251 mmol) in 600 mL of THF at −78° C. was dropwise added LiHMDS (1.0 Min THF, 325 mL, 325 mmol), then the mixture was stirred for 1 h at −78°C. before the addition of PhN(OTf)₂ (98.5 g, 276 mmol) at −78° C. Thereaction was allowed to warm to room temperature and stirred overnight.The solution was quenched with water (100 mL) and the aqueous phase wasextracted with EtOAc (200 mL×3). The extracts were washed with brine(500 mL) and dried over Na₂SO₄. The solution was evaporated in vacuum togive crude tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(80.8 g, yield: 97%) as yellow oil, which was used for next step withoutfurther purification.

Step 2: To a solution of tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(2.5 g, 7.55 mmol) in dioxane (10 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4′,4′,5′,5′-tetramethyl-1,3,2-dioxaborolane(2.9 g, 11.3 mmol), KOAc (1.5 g, 15.1 mmol) and Pd(dppf)Cl₂ under N₂.The mixture was stirred at 80° C. overnight. After cooled to roomtemperature, the reactant was concentrated to dryness and the residuewas purified by silica gel column (PE/EA=20/1) to give tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2 g, yield: 86%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=6.38(s, 1H), 3.86 (s, 2H), 3.36-3.28 (m, 2H), 2.09-2.05 (m, 2H), 1.44 (s,9H), 1.11 (s, 12H).

Step 3: To a solution of 3-methoxythiophene (5.0 g, 43.8 mmol) in DCM(50 mL) was added NBS (7.8 g, 43.8 mmol) at 0° C. and the the mixturewas stirred at this temperature for 0.5 h. The reaction was quenchedwith water (20 mL) and the mixture was extracted with DCM (30 mL×3). Theextracts were dried over Na2SO4 and concentrated to give2-bromo-3-methoxythiophene (8 g, yield: 95%) as a black oil. Note: thisproduct goes bad easily in pure form at room temperature. But it iscomparatively stable in solution. ¹H NMR (400 MHz, DMSO-d6): δ=7.58 (d,J=6.0 Hz, 1H), 7.02 (d, J=6.0 Hz, 1H), 3.84 (s, 3H).

Step 4: To a solution of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(500 mg, 2.6 mmol) in DMF (10 mL) was added 2-bromo-3-methoxythiophene(1.0 g, 3.9 mmol), Cs₂CO₃ (2.53 g, 7.8 mmol) and Pd(dppf)Cl₂.CH₂Cl₂(205mg, 0.26 mmol). The mixture was stirred at 100° C. under N₂ overnight.The reactant was concentrated to dryness. The residue was combined withanother batch (200 mg of 2-bromo-3-methoxythiophene) and the residue waspurified by silica gel column (PE/EtOAc=20/1) to afford tert-butyl4-(3-methoxythiophen-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (400mg, yield: 13%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d6): δ=7.34 (d,J=5.6 Hz, 1H), 7.04 (d, J=5.6 Hz, 1H), 6.38 (s, 1H), 3.98-3.94 (m, 2H),3.81 (s, 3H), 3.48 (t, J=5.2 Hz, 2H), 2.44-2.38 (m, 2H), 1.40 (s, 9H).

Step 5: To a solution of tert-butyl4-(3-methoxythiophen-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (400mg, 1.35 mmol) in MeOH (10 mL) was added 10% wet Pd/C (0.2 g), and thesuspension was stirred at room temperature under balloon pressureovernight. The suspension was filtered and the filtrate was concentratedto give tert-butyl 4-(3-methoxythiophen-2-yl)piperidine-1-carboxylate(400 mg, yield: 99%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ=7.01(d, J=5.2 Hz, 1H), 6.81 (d, J=5.2 Hz, 1H), 4.20-4.15 (m, 2H), 3.85 (s,3H), 3.10-3.01 (m, 1H), 2.82 (t, J=12.4 Hz, 2H), 1.88 (d, J=13.2 Hz,2H), 1.62-1.50 (m, 2H), 1.46 (s, 9H).

Step 6: To a solution of tert-butyl4-(3-methoxythiophen-2-yl)piperidine-1-carboxylate (300 mg, 1.01 mmol)in DCM (10 mL) was added TFA (2 mL), and the mixture was stirred at roomtemperature for 2 h. The reactant was concentrated to afford4-(3-methoxythiophen-2-yl)piperidine as a dark oil. MS: m/z 198.2(M+H⁺).

Step 7: A mixture of compound 4-(3-methoxythiophen-2-yl)piperidine (125mg, 0.424 mmol),2-cyclopropyl-6-((2-hydroxyethyl)(methyl)amino)quinazolin-4-ol (100 mg,0.386 mmol), BOP (256 mg, 0.580 mmol) and DBU (235 mg, 1.54 mmol) inacetonitrile (20 mL) was stirred room temperature overnight. LCMS showedthe reaction was completed. Then the reaction mixture was poured intoice-water (100 mL), and the mixture was extracted with EtOAc (50 mL×3).The combined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by Prep-HPLC to afford2-((2-cyclopropyl-4-(4-(3-methoxythiophen-2-yl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol(12 mg, yield: 7%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃):δ=7.77-7.70 (m, 1H), 7.34 (dd, J=9.2, 3.2 Hz, 1H), 7.04 (d, J=5.6 Hz,1H), 6.92 (s, 1H), 6.85 (d, J=5.2 Hz, 1H), 4.33-4.30 (m, 2H), 3.88-3.85(m, 5H), 3.56-3.53 (m, 2H), 3.26-3.24 (m, 3H), 3.04 (s, 3H), 1.92-1.86(m, 5H), 1.17-1.13 (m, 2H), 0.99-0.97 (m, 2H). MS: m/z 439.2 (M+H⁺).

Example 191: Preparation of2-({2-Cyclopropylethynyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: A mixture of compound2-chloro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline (600mg, 1.51 mmol), ethynyl-cyclopropane (573 mg, 7.54 mmol), CuI (60 mg,030 mmol), TEA (457 mg, 4.52 mmol) and Pd(PPh₃)₄ (175 mg, 0.15 mmol) inDMF (20 mL) was charged with N₂ for 3 times, and the resulting mixturewas heated to 100° C. overnight. LCMS showed the reaction was completed.The reaction mixture was concentrated to give the crude product whichwas purified by silica gel column chromatography (PE/EtOAc=1/1-5/1) toafford2-(cyclopropylethynyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline(500 mg, 77% yield) as a brown solid. MS: m/z 429.2 (M+H⁺).

Step 2: A suspension of2-(cyclopropylethynyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline(500 mg, 1.17 mmol) and iron powder (327 mg, 5.84 mmol) in a mixture ofMeOH (20 mL) and sat.NH₄Cl (2 mL) was heated to reflux for 30 min. LCMSshowed the reaction was completed. The reaction suspension wasconcentrated to dryness. The residue was diluted with water (100 mL),and the mixture was extracted with EtOAc (100 mL×2). The extracts werewashed brine (100 mL), dried over Na₂SO₄, filtered and concentrated togive the crude2-(cyclopropylethynyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-amine(500 mg, yield: 95%) as a brown solid. MS: m/z 399.2 (M+H⁺).

Step 3: A suspension of2-(cyclopropylethynyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-amine(500 mg, 1.17 mmol), 2-bromo-ethanol (220 mg, 1.76 mmol) and K₂CO₃ (486mg, 3.51 mmol) in DMF (10 mL) was heated to 100° C. for overnight. LCMSshowed the reaction was completed. The reaction was diluted with water(100 mL), and the mixture was extracted with EtOAc (100 mL×2). Thecombined organic layers were washed with brine (100 mL×3), dried overNa₂SO₄, filtered and concentrated to give the crude2-((2-(cyclopropylethynyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(600 mg, about 60% purity, 40% yield) as a brown solid. MS: m/z 443.2(M+H⁺).

Step 4: To a solution of2-((2-(cyclopropylethynyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(crude 600 mg, 1.357 mmol) in MeOH (20 mL) was added HCHO (1.0 mL),followed by NaBH₃CN (0.85 g, 13.57 mmol) and HOAc (0.68 g, 13.57 mmol),and the resulting mixture was stirred at room temperature overnight.LCMS showed the reaction was completed. The reaction mixture wasconcentrated, and the residue was diluted with water (100 mL). Themixture was extracted with EtOAc (100 mL×2). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated to give the crudeproduct which was purified by Prep-HPLC to afford24(2-(cyclopropylethynyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol(20 mg, yield: 5%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ=7.77(d, J=8.8 Hz, 1H), 7.36 (dd, J=9.2 Hz, 2.8 Hz, 1H), 7.25-7.21 (m, 2H),6.99-6.89 (m, 3H), 4.44-4.40 (m, 2H), 3.89-3.88 (m, 5H), 3.60-3.57 (m,2H), 3.53-3.51 (m, 3H), 3.07 (s, 3H), 1.95-1.91 (m, 4H), 1.53-1.50 (m,1H), 0.99-0.96 (m, 2H), 0.91-0.88 (m, 2H). MS: m/z 457.2 (M+H⁺).

Example 192: Preparation of2-({2-Ethynyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: A mixture of2-chloro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline (800mg, 2.01 mmol), 2-methyl-but-3-yn-2-ol (845 mg, 10.05 mmol), CuI (76 mg,0.04 mmol), TEA (610 mg, 6.03 mmol) and Pd(PPh₃)₄ (230 mg, 0.02 mmol) inDMF (20 mL) was charged with N₂ 3 times, and the resulting mixture washeated to 100° C. for overnight. LCMS showed the reaction was completed.The reaction mixture was concentrated to give the crude product whichwas purified by silica gel column chromatography (PE/EtOAc=1/1-5/1) toafford the desired4-(4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazolin-2-yl)-2-methylbut-3-yn-2-ol(520 mg, yield: 58%) as a brown solid.

Step 2: A suspension of4-(4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazolin-2-yl)-2-methylbut-3-yn-2-ol(520 mg, 1.16 mmol) and iron powder (326 mg, 5.83 mmol) in a mixture ofMeOH (20 mL) and sat.NH₄Cl (2 mL) was heated to reflux for 30 min. LCMSshowed the reaction was completed. The reaction suspension wasconcentrated, and the residue was diluted with water (100 mL). Themixture was extracted with EtOAc (100 mL×2). The combined organic layerswere washed brine (100 mL), dried over Na₂SO₄, filtered and concentratedto give the crude4-(6-amino-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-2-yl)-2-methylbut-3-yn-2-ol(540 mg, yield: 80%) as a brown solid.

Step 3: To solution of4-(6-amino-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-2-yl)-2-methylbut-3-yn-2-ol(440 mg, 1.06 mmol) in toluene (50 mL) was added ground NaOH (850 mg,21.20 mmol), and the resulting suspension was heated to 110° C. for 2 h.LCMS showed the reaction was completed. The reaction suspension wasfiltered and the filtrate was concentrated to give2-((2-ethynyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(350 mg, yield: 78%) as a brown solid.

Step 4: A suspension of2-((2-ethynyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(170 mg, 0.475 mmol), (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (568mg, 2.373 mmol) and Cs₂CO₃ (773 mg, 2.373 mmol) in DMF (10 mL) washeated to 150° C. for 2 h. LCMS showed the reaction was completed. Thereaction suspension was diluted with ice-water (100 mL), and the mixturewas extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (50 mL×3), dried over Na₂SO₄, filtered andconcentrated to give the crude product which was purified by silica gelcolumn chromatography (PE/EtOAc=3/1) to afford2-((2-ethynyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(64 mg, yield: 19%) as a brown solid.

Step 5: To a solution of2-((2-ethynyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(64 mg, 0.124 mmol) in MeOH (10 mL) was added HCHO (0.2 mL), followed byNaBH₃CN (39 mg, 0.62 mmol) and NaBH(OAc)₃ (131 mg, 0.62 mmol), and theresulting mixture was stirred at room temperature for overnight. Thereaction mixture was concentrated, and the residue was diluted withwater (50 mL). The mixture was extracted with EtOAc (30 mL×3). Thecombined organic layers were washed brine (100 mL), dried over Na₂SO₄,filtered and concentrated to give the desired productN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-ethynyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methylquinazolin-6-amine(crude 100 mg, yield: 90%) as a yellow solid.

Step 6: A mixture ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-ethynyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methylquinazolin-6-amine(crude 100 mg, 0.194 mmol) and TBAF (253 mg, 0.968 mmol) in THF (10 mL)was stirred at room temperature for 2 h. LCMS showed the reaction wascompleted. The reaction mixture was diluted with sat.NH₄Cl (50 mL), andthe mixture was extracted with EtOAc (30 mL×3). The combined organiclayers were washed brine (100 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product which was purified by Prep-TLC(PE/EtOAc=1/1) to afford2-((2-ethynyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol(17 mg, 21% yield) as a yellow solid. NMR (400 MHz, DMSO-d6): δ=7.77 (d,J=9.6 Hz, 1H), 7.40 (dd, J=9.2 Hz, 2.8 Hz, 1H), 7.25-7.21 (m, 2H),6.99-6.89 (m, 3H), 4.42-4.39 (m, 2H), 3.90-3.86 (m, 5H), 3.62-3.59 (m,2H), 3.22-3.12 (m, 3H), 3.09 (s, 3H), 2.98 (s, 1H), 2.03-1.92 (m, 4H).MS: m/z 417.2 (M+H⁺).

Example 193: Preparation of2-((2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol

Step 1: To a suspension of NaH (60% in mineral oil, 110 mg, 2.76 mmol)in THF (20 mL) was added cyclobutanol (181 mg, 2.51 mmol), and thereaction was stirred at 0° C. for 30 min. Then to the mixture was added2-chloro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline (500mg, 1.26 mmol), and the mixture was stirred at room temperature till2-chloro-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline wasconsumed completely shown by TLC. The reaction was quenched withsaturated NH₄Cl (100 mL). The aqueous phase was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine (100 mL) anddried over Na₂SO₄. The solution was filtered and concentrated to give2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline(540 mg crude, 80% LC purity, yield: 79%) as a brown solid.

Step 2: To a solution of2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-nitroquinazoline(540 mg crude, 1.24 mmol) in MeOH (30 mL) was added iron (330 mg, 6.22mmol) and saturated NH₄Cl (5 mL), and the mixture was stirred at 80° C.till the reaction was completed shown by TLC. The reaction wasconcentrated and the residue was diluted with water (100 mL). Themixture was extracted with DCM (50 mL×3). The combined organic layerswere washed with brine (100 mL) and dried over Na₂SO₄. The solution wasfiltered and concentrated to give2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-amine(530 mg crude) as a yellow solid.

Step 3: To a solution of2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-amine(530 mg crude, 1.31 mmol) in MeOH (30 mL) was added ethyl 2-oxoacetate(345 mg, 3.92 mmol), NaBH₃CN (266 mg, 3.92 mmol) and NaOAc (190 mg, 3.92mmol), and the mixture was stirred at room temperature for 1 h. LCMSshowed the reaction was completed. The reactant was concentrated and theresidue was diluted with water (100 mL). The mixture was extracted withDCM (50 mL×3). The extracts were washed with brine (100 mL) and driedover Na₂SO₄. The solution was filtered and concentrated to give2-((2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)aceticacid (800 mg crude) as a yellow solid. MS: m/z 463.2 (M+H⁺).

Step 4: A mixture of2-((2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)aceticacid (800 mg crude, 1.72 mmol) and BH₃.Me₂S (8.5 mL, 17.3 mmol) in THF(20 mL) was heated to reflux overnight. The reaction was quenched withMeOH (10 mL), followed by 1N HCl (20 mL). The mixture was refluxed for 1h. After cooled to room temperature, the reaction was extracted withEtOAc (50 mL×3). The extracts were washed with brine (100 mL) and driedover Na₂SO₄. The solution was filtered and concentrated to give2-((2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(600 mg crude) as a yellow solid. MS: m/z 449.2 (M+H⁺).

Step 5: A mixture of2-((2-cyclobutoxy-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)amino)ethanol(600 mg crude, 1.34 mmol), HCHO (1.0 mL), NaBH₃CN (0.84 g, 13.4 mmol)and NaBH(OAc)₃ (2.84 g, 13.4 mmol) in MeOH (50 mL) was stirred at roomtemperature till LCMS showed the reaction was completed. The reactionmixture was concentrated and the residue was diluted with ice water (100mL). The mixture was extracted with DCM (50 mL×3). The extracts werewashed with brine (100 mL) and dried over Na₂SO₄. The solution wasfiltered and concentrated to give2-({2-Cyclobutoxy-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol(55 mg, five-step yield: 9.4%) as a yellow solid. ¹H NMR (400 MHz,CDCl3): δ=7.62 (d, J=9.2 Hz, 1H), 7.35 (dd, J=9.2 Hz, 1H), 7.24-7.20 (m,3H), 7.02-6.87 (m, 3H), 5.30-5.23 (m, 1H), 4.52-4.47 (m, 2H), 3.87-3.82(m, 5H), 3.53-3.48 (m, 2H), 3.30-3.25 (m, 3H), 3.01 (s, 3H), 2.51-2.46(m, 2H), 2.31-2.25 (m, 2H), 1.99-1.92 (m, 6H). MS: m/z 423.2 (M+H⁺).

Example 194: Preparation of2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methyl-N-(2-morpholinoethyl)pyrido[3,4-d]pyrimidin-6-amine

Step 1: A mixture of 2-morpholinoethanamine (1.00 g, 7.69 mmol), (Boc)₂O(1.66 g, 7.69 mmol) and TEA (0.93 g, 9.23 mmol) in DCM (50 mL) wasstirred at room temperature for overnight. The reaction mixture wasdiluted with water (100 mL). The aqueous phase was extracted with DCM(100 mL×2), and the combined organic layers were washed with brine (100mL), dried over Na₂SO₄, filtered and concentrated to give tert-butyl(2-morpholinoethyl)carbamate (1.60 g, yield: 90%) as yellow oil.

Step 2: To a solution of tert-butyl (2-morpholinoethyl)carbamate (1.0 g,4.4 mmol) in THF (50 mL) was added LAH (0.5 g, 13 mmol), and theresulting suspension was heated to reflux for overnight. TLC showed thereaction was completed. The reaction suspension was cooled to 0° C., andthen quenched with water (3.0 mL), followed by 5 N NaOH (2.0 mL). Theresulting suspension was filtered and the filtrate was concentrated togive N-methyl-2-morpholinoethanamine (0.35 g, yield: 55%) as yellow oil.

Step 3: A mixture of6-chloro-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)pyrido[3,4-d]pyrimidine(50 mg, 0.127 mmol), N-methyl-2-morpholinoethanamine (37 mg, 0.254 mmol)and DIPEA (30 mg, 0.280 mmol) in NMP (5 mL) was heated to 180° C. in MWfor 5 h. LCMS showed the reaction was completed. The reaction mixturewas diluted with water (20 mL). The aqueous phase was extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine (50mL×3), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified by Prep-HPLC to afford the desired2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methyl-N-(2-morpholinoethyl)pyrido[3,4-d]pyrimidin-6-amine(15 mg, yield: 24%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.90(s, 1H), 7.21 (d, J=8.0 Hz, 2H), 6.98-6.89 (m, 2H), 6.50 (s, 1H),4.44-4.41 (m, 2H), 3.86-3.80 (m, 5H), 3.69-3.67 (m, 4H), 3.32-3.29 (m,1H), 3.19-3.12 (m, 2H), 3.09 (s, 3H), 2.60- 2.52 (m, 6H), 1.99-1.96 (m,4H), 1.15-1.12 (m, 2H), 0.99-0.95 (m, 2H). MS: m/z 503.3 (M+H⁺).

Example 195: Preparation of2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol

Step 1: To a solution of 2-chloro-4-methyl-5-nitro-pyridine (10.35 g, 60mmol) in H₂S O₄ (100 mL), CrO₃ (19.8 g, 198 mmol) was added at 0° C. Themixture was stirred at 0° C. for 1 h and then was allowed to warm toroom temperature and stirred overnight. The mixture was poured into icewater (500 mL). The resulting solid was filtered and dried to give2-chloro-5-nitro-isonicotinic acid (8.89 g, yield: 73%) as a whitesolid. MS: m/z 200.9 (M−H⁺).

Step 2: To a solution of 2-chloro-5-nitro-isonicotinic acid (4.64 g, 23mmol) in DCM (200 mL), 5 drops of DMF was added. Then (COCl)₂(7.27 g,57.3 mmol) was added dropwise at 0° C. The mixture was stirred at roomtemperature overnight. The solvent was removed and dry THF (200 mL) wasadded. NH₃ gas was bubbled into the solution for 0.5 h. The mixture wasfiltered and the filtrate was concentrated to give2-chloro-5-nitro-isonicotinamide (4.61 g, 95%) as a white solid. ¹H NMR(400 MHz, DMSO-d6): δ=9.12 (s, 1H), 8.32 (brs, 1H), 8.07 (brs, 1H), 7.90(s, 1H).

Step 3: To a solution of 2-chloro-5-nitro-isonicotinamide (1.0 g, 5.0mmol) in 1,4-dioxane (40 mL), DIEPA (1.3 g, 10 mmol) and2-methylamino-ethanol (1.13 g, 15 mmol) was added. The mixture wasstirred at 90° C. overnight. The solvent was removed to give2-[(2-hydroxy-ethyl)-methyl-amino]-5-nitro-isonicotinamide (2.3 g crude)as yellow oil. MS: m/z 238.9 (M−H⁺).

Step 4: To a solution of2-[(2-hydroxy-ethyl)-methyl-amino]-5-nitro-isonicotinamide (2.3 g,crude) in pyridine (5 mL), Ac₂O (1.53 g, 15 mmol) was added. The mixturewas stirred at 100° C. for 1 h. The solvent was removed and the residuewas purified by silica gel column (DCM/MeOH=40/1) to give2-((4-carbamoyl-5-nitropyridin-2-yl)(methyl)amino)ethyl acetate (0.99 g,two-step yield: 70%) as a yellow solid. MS: m/z 282.9 (M+H⁺).

Step 5: To a solution of2-((4-carbamoyl-5-nitropyridin-2-yl)(methyl)amino)ethyl acetate (0.99 g,3.5 mmol) in MeOH (30 mL), Pd/C (0.3 g) was added. The mixture wasstirred at room temperature under H₂ balloon for 4 h. The mixture wasfiltered and the filtrate was concentrated to give2-((5-amino-4-carbamoylpyridin-2-yl)(methyl)amino)ethyl acetate (0.81 g,yield: 92%) as brown oil. MS: m/z 253.0 (M+H⁺).

Step 6-8: These three steps are similar to2-((8-chloro-2-(1-fluorocyclobutyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanolto afford2-({2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyridopyrimidin-6-yl}-methyl-amino)-ethanol (31 mg, three-step yield: 3.1%) asa yellow solid. ¹H NMR (300 MHz, CDCl₃): δ=9.00 (s, 1H), 7.25-7.20 (m,2H), 6.97-6.92 (m, 2H), 6.61 (s, 1H), 4.45 (d, J=12.4 Hz, 2H), 3.90-3.83(m, 7H), 3.20-3.14 (m, 3H), 3.12 (s, 3H), 2.02-1.63 (m, 4H), 1.58-1.49(m, 4H). MS: m/z 452.2 (M+H⁺).

Example 196: Preparation of1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol

The title compound was prepared using general procedure for2-({2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol.¹HNMR (400 MHz, CDCl₃): δ=9.07 (s, 1H), 7.24-7.20 (m, 2H), 6.98-6.89 (m,2H), 6.42 (s, 1H), 4.67 (brs, 1H), 4.45 (d, J=12.4 MHz, 2H), 3.86 (s3H), 3.73-3.59 (m, 4H), 3.33-3.28 (m, 1H), 3.20-3.14 (m, 2H), 2.24.2.20(m, 1H), 2.02-1.60 (m, 5H), 1.54-1.48 (m, 4H). MS: m/z 464.2 (M+H⁺).

Example 197: Preparation of1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol

The title compound was prepared using general procedure for2-({2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=9.07 (s, 1H), 7.26-7.21 (m, 2H), 6.96-6.89(m, 2H), 6.42 (s, 1H), 4.69-4.65 (m, 1H), 4.45 (d, J=12.4 MHz, 2H), 3.86(s 3H), 3.72-3.59 (m, 4H), 3.20-3.14 (m, 3H), 2.23-2.14 (m, 1H),2.00-1.85 (m, 5H), 1.59-1.45 (m, 4H). MS: m/z 464.2 (M+H⁺).

Example 198: Preparation of2-({2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol

The title compound was prepared using general procedure for2-({2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=9.00 (s, 1H), 7.25-7.21 (m, 2H), 6.98-6.89(m, 2H), 6.42 (s, 1H), 4.57 (d, J=12.4 MHz, 2H), 3.91-3.82 (m, 4H), 3.86(s, 3H), 3.34-3.23 (m, 3H), 3.14 (s, 3H), 2.85-2.83 (m, 2H), 2.69-2.61(m, 2H), 2.05-1.90 (m, 6H). MS: m/z 466.2 (M+H⁺).

Example 199: Preparation of1-{2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol

The title compound was prepared using general procedure for2-({2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=9.07 (s, 1H), 7.25-7.20 (m, 2H), 6.96-6.89(m, 2H), 6.44 (s, 1H), 4.70-4.66 (m, 1H), 4.57 (d, J=12.4 Hz, 2H), 3.86(s, 3H), 3.71-3.61 (m, 4H), 3.35-3.20 (m, 3H), 2.88-2.64 (m, 4H),2.24-2.20 (m, 4H), 2.05-1.91 (m, 4H). MS: m/z 478.2 (M+H⁺).

Example 200: Preparation of1-{2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol

The title compound was prepared using general procedure for2-({2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=9.07 (s, 1H), 7.25-7.22 (m, 2H), 6.97-6.89(m, 2H), 6.44 (s, 1H), 4.70-4.66 (m, 1H), 4.58 (d, J=12.4 Hz, 2H), 3.86(s, 3H), 3.73-3.60 (m, 4H), 3.30-3.22 (m, 3H), 2.86-2.64 (m, 4H),2.22-2.04 (m, 2H), 2.01-1.69 (m, 6H). MS: m/z 478.2 (M+H⁺).

Example 201: Preparation of2-({8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: To a solution of 2-amino-5-bromo-3-chloro-benzonitrile (3.50 g,17.0 mmol) and NaOH (1.4 g, 34.0 mmol in MeOH/H₂O (1/5, 70 mL) was addedH₂O₂ (18.5 mL, 170.0 mmol) at room temperature. The mixture was stirredat 90° C. overnight. After cooled to room temperature, the mixture wasdiluted with H₂O (50 mL) and filtered. The filter cake was dried to give2-amino-5-bromo-3-chloro-benzamide (3.2 g, yield: 85%) as a white solid.NMR (400 MHz, DMSO-d₆): δ=8.03 (brs, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.59(d, J=2.0 Hz, 1H), 7.44 (brs, 1H), 6.84 (brs, 2H).

Step 2: To a mixture of 1-fluoro-cyclopropanecarboxylic acid (300 mg,2.88 mmol) in DCM (5 mL) was added (COCl)₂ (439.0 mg, 3.46 mmol) and themixture was stirred 38° C. for 2 h. Then, the mixture was added to thesolution of 2-amino-5-bromo-3-chloro-benzamide (794.0 mg, 3.2 mmol) inpyridine (10 mL). The mixture was stirred at 80° C. overnight. Then, themixture was concentrated and the residue was purified by flash column togive5-bromo-3-chloro-2-[(1-fluoro-cyclopropanecarbonyl)-amino]-benzamide(450 mg, yield: 47%) as a white solid. MS: m/z 333.0 (M−H⁺).

Step 3: The mixture of5-bromo-3-chloro-2-[(1-fluoro-cyclopropanecarbonyl)-amino]-benzamide(450.0 mg, 1.4 mmol) and NaOH (190.0 mg, 2.7 mmol) in THF/H₂O (5:1, 10mL) was refluxed for 12 h. Then, the mixture was concentrated and theresidue was purified by flash column to give6-bromo-8-chloro-2-(1-fluoro-cyclopropyl)-quinazolin-4-ol (330 mg,yield: 78%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ=12.94 (s,1H), 8.19 (d, J=2.4 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 1.64-1.15 (m, 4H)

Step 4: The mixture of6-bromo-8-chloro-2-(1-fluoro-cyclopropyl)-quinazolin-4-ol (110.0 mg,0.35 mmol), 2-methylamino-ethanol (52.0 mg, 0.70 mmol), K₂CO₃ (120.0 mg,0.87 mmol), L-proline (32 mg, 0.28 mmol) and CuI (26.0 mg, 0.14 mmol) inDMSO (2 mL) was heated to 90° C. by microwave for 5 h. The reactionmixture was filtered and the filtrate was purified by pre-HPLC to give8-chloro-2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(34.0 mg, yield: 31%) as a yellow solid. MS: m/z 309.9 (M−H⁺).

Step 5: A mixture of8-chloro-2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(34.0 mg, 0.11 mmol), 4-(2-methoxy-phenyl)-piperidine (191.0 mg, 0.22mmol), BOP (99.0 mg, 0.22 mmol) and DBU (68 mg, 0.44 mmol) in MeCN wasstirred at room temperature overnight. The mixture was concentrated andthe residue was purified by pre-HPLC to give2-({8-chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol(4.2 mg, yield: 7.5%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=7.48(d, J=2.4 Hz, 1H), 7.25-7.20 (m, 2H), 6.96 (t, J=7.6 Hz, 1H), 6.91-6.87(m, 2H), 4.33 (d, J=12.8 Hz, 2H), 3.88-3.85 (m, 5H), 3.55 (t, J=2.4 Hz,2H), 3.48 (m, 1H), 3.15 (t, J=11.6 Hz, 2H), 3.05 (s, 3H), 1.99-1.87 (m,4H), 1.75-1.69 (m, 2H), 1.58-1.46 (m, 2H). MS: m/z 485.2 (M+H⁺).

Example 202: Preparation of1-{8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol

The title compound was prepared as described in example2-({8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.30-7.29 (m, 1H), 7.26-7.21 (m, 2H),7.00-6.90 (m, 2H), 6.67-6.66 (d, J=2.7 Hz, 1H), 4.69-4.68 (m, 1H),4.38-4.37 (d, J=12.8 Hz, 2H), 3.87 (s, 3H), 3.64-3.60 (m, 2H), 3.49-3.45(m, 1H), 3.38-3.28 (m, 2H), 3.18-3.10 (m, 2H), 2.26-2.16 (m, 2H),2.03-1.91 (m, 5H), 1.56-1.48 (m, 4H). MS: m/z 497.2 (M+H⁺).

Example 203: Preparation of1-{8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol

The title compound was prepared as described in example2-({8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (300 MHz, CDCl₃): δ=7.30-7.20 (m, 3H), 6.96 (t, J=7.6 Hz, 1H),6.90 (d, J=3.6 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 4.69-4.68 (m, 1H),4.36-4.33 (d, J=12.8 Hz, 2H), 3.85 (s, 3H), 3.62-3.58 (m, 2H), 3.47-3.42(m, 1H), 3.36-3.26 (m, 2H), 3.16-3.10 (m, 2H), 2.24-2.12 (m, 2H),2.03-1.89 (m, 5H), 1.54-1.45 (m, 4H). MS: m/z 497.2 (M+H⁺).

Example 204: Preparation of2-{[8-Fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol

Step 1: A suspension of 2-amino-3-fluoro-benzonitrile (5.4 g, 40.0 mmol)and NBS (7.1 g, 40.0 mmol) in DCM (150 mL) was stirred at roomtemperature for overnight. TLC showed the reaction was completed. Thereaction was quenched with Na₂SO₃ (aq, 50 mL), and the mixture wasextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine (150 mL), dried over Na₂SO₄, filtered and concentrated togive 2-amino-5-bromo-3-fluoro-benzonitrile (8.8 g, yield: 99.5%) aswhite solid. ¹H NMR (DMSO-d₆, 400 MHz): δ=7.60 (dd, J=12.4, 1.2 Hz, 1H),7.53 (s, 1H), 6.44 (brs, 2H). MS: m/z 214.0 (M+H⁺).

Step 2: To a solution of 1-methyl-cyclopropanecarboxylic acid (200 mg,2.00 mmol) in oxalyl chloride (0.2 mL) was added DMF (0.05 mL). Themixture was stirred at room temperature for 2 h. To a solution of2-amino-5-bromo-3-fluoro-benzonitrile (513 mg, 2.40 mmol), pyridine (2.0mL) in THF (10 mL) was added a solution of 1-methyl-cyclopropanecarbonylchloride in THF (10 mL). The resulting mixture was stirred at roomtemperature for 2 h. The resultant was added to NaHCO₃ (50 mL) and theaqueous phase was extracted with EtOAc (40 mL×3). The organic layer waswashed with brine (50 mL) and dried over Na₂SO₄. The solvent was removedin vacuum to afford 1-methyl-cyclopropanecarboxylic acid(4-bromo-2-cyano-6-fluoro-phenyl)-amide (500 mg, yield: 84%) as a yellowsolid.

Step 3: To a solution of 1-methyl-cyclopropanecarboxylic acid(4-bromo-2-cyano-6-fluoro-phenyl)-amide (500 mg, 1.68 mmol) in ethanol(20 mL) was added H₂O₂ (3 mL) and NaOH (80 mg, 2.01 mmol). The mixturewas stirred at 80° C. for 1 h. The solvent was removed in vacuum. Water(100 mL) was added. The mixture was extracted with DCM (30 mL×3). Theorganic layer was washed with brine (50 mL), dried over Na₂SO₄ andconcentrated to give6-bromo-8-fluoro-2-(1-methyl-cyclopropyl)-quinazolin-4-ol (298 mg,yield: 60%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz): δ=12.06-11.99(brs, 1H), 7.95-7.92 (m, 2H), 1.46 (s, 3H), 1.28-1.25 (m, 2H), 0.83-0.77(m, 2H). MS: m/z 296.0 (M+H⁺)

Step 4: To a solution of6-bromo-8-fluoro-2-(1-methyl-cyclopropyl)-quinazolin-4-ol (298 mg, 1.00mmol) L-proline (115 mg, 1.00 mmol), CuI (96 mg, 0.50 mmol) and K₂CO₃(553 mg, 4.00 mmol) in DMSO (5 mL) were added 2-methylamino-ethanol (226mg, 3.00 mmol) under N₂. The reaction was stirred at 100° C. forovernight. LCMS showed the reaction was good. The reaction was quenchedwith water (10 mL), and the mixture was extracted with EtOAc (15 mL×3).The organic layer was washed with brine (15 mL), dried over Na₂SO₄, andevaporated in vacuum. The residue was purified by silica gelchromatography (EA/PE=1/5) to give8-fluoro-6-[(2-hydroxy-ethyl)-methyl-amino]-2-(1-methyl-cyclopropyl)-quinazolin-4-ol(140 mg, yield: 48%) as yellow solid.

Step 5: To a suspension of 2-methoxy-3-piperidin-4-yl-pyrazine (121 mg,0.53 mmol), BOP (314 mg, 0.73 mmol),8-fluoro-6-[(2-hydroxy-ethyl)-methyl-amino]-2-(1-methyl-cyclopropyl)-quinazolin-4-olin MeCN (10 mL) was added DBU (367 mg, 2.41 mmol), then the mixture wasstirred at room temperature for overnight. TLC showed the reaction wascompleted. The reaction was quenched with water (20 mL), and the mixturewas extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄. The solution was filteredand concentrated to dryness in vacuum. The residue was purified byPrep-HPLC to give2-{[8-fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol(45 mg, yield: 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.07(s, 1H), 7.97 (s, 1H), 7.06 (d, J=12.8 Hz, 1H), 6.73 (s, 1H), 4.29 (d,J=12.4 Hz, 2H), 4.00 (s, 3H), 3.86 (s, 2H), 3.52 (s, 2H), 3.32-3.29 (m,1H), 3.14-3.03 (m, 5H), 2.13-1.99 (m, 4H), 1.71 (s, 3H), 1.44-1.38 (m,2H), 0.83-0.77 (m, 2H). MS: m/z 466.9 (M+H⁺)

Example 205: Preparation of2-{[4-[4-(3-Methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described in example2-{[8-fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.08 (d, J=2.8 Hz, 1H), 7.97 (d, J=2.8 Hz,1H), 7.76 (d, J=8.4 Hz, 1H), 7.37-7.34 (m, 1H), 7.98 (d, J=2.8 Hz, 1H),4.30 (d, J=12.8 Hz, 2H), 4.00 (s, 3H), 3.87-3.84 (m, 2H), 3.55-3.53 (m,2H), 3.34-3.28 (m, 1H), 3.15-2.93 (m, 5H), 2.14-1.99 (m, 4H), 1.67 (s,3H), 1.41-1.40 (m, 2H), 0.81-0.78 (m, 2H). MS: m/z 448.9 (M+H⁺).

Example 206: Preparation of2-{[2-(1-Fluoro-cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-V-yl)-quinazolin-6-yl}-methyl-amino]-ethanol

Step 1: To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.45 g, 4.68 mmol) and 2-bromo-3-methoxy-pyridine(800 mg, 4.26 mmol) in dioxane/H₂O (30 mL+10 mL) were added Pd(dppf)Cl₂(156 mg, 0.21 mmol) and K₂CO₃ (2.35 g, 17.0 mmol). The resulting mixturewas stirred at 80° C. under N₂ atmosphere overnight. Then the reactionmixture was poured into H₂O (100 mL) and extracted with EtOAc (20 mL×3).The extracts were washed with brine (20 mL×3), dried over Na₂SO₄ andconcentrated in vacuum to give a residue, which was purified by a silicagel column (DCM/MeOH=50/1) to afford3-methoxy-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (1.12 g, yield: 91%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ=8.18 (dd, J=4.4, 1.2 Hz, 1H), 7.22-7.11 (m, 2H), 6.58-6.30 (m,1H), 4.18-4.08 (m, 2H), 3.84 (s, 3H), 3.67-3.57 (m, 2H), 2.70-2.60 (m,2H), 1.49 (s, 9H).

Step 2: To a solution of3-methoxy-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (1.12 g, 3.79 mmol) in MeOH (20 mL) was added wet Pd/C(110 mg, 10% wt). The resulting mixture was stirred at room temperatureunder H₂ atmosphere overnight. Then Pd/C was filtered off and thefiltrate was concentrated in vacuum to afford3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-F-carboxylic acidtert-butyl ester (1.1 g, yield: 100%) as a colorless oil, which was usedfor next step without further purification.

Step 3: To a solution of3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (1.1 g, 3.76 mmol) in EtOAc (20 mL) was addedHCl/EtOAc (excess). The resulting mixture was stirred at roomtemperature for 4 hrs. The solid precipitated form the reaction mixturewas collected by filtration. The cake was washed with EtOAc (60 mL),ether (60 mL) and air-dried to afford3-methoxy-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl (630 mg, yield:73%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.62-9.43 (m, 1H),9.32-9.10 (m, 1H), 8.27 (d, J=4.4 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.69(t, J=5.6 Hz, 1H), 3.96 (s, 3H), 3.53 (t, J=11.2 Hz, 1H), 3.41-3.31 (m,2H), 3.10-2.92 (m, 2H), 2.32-2.12 (m, 2H), 2.01-1.85 (m, 2H), 1.98-1.89(m, 4H).

Step 4: To a mixture of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(100 mg, 0.361 mmol) and3-methoxy-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl (91 mg, 0.397mmol) in MeCN (20 mL) were added BOP (240 mg, 0.542 mmol) and DBU (220mg, 1.44 mmol). The resulting mixture was stirred at room temperatureovernight. Then MeCN was removed in vacuum to give a residue, which waspurified by Prep-HPLC with NH₄OH as additive to afford2-{[2-(1-Fluoro-cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol(20.7 mg, yield: 13%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.16(t, J=2.8 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.37 (dd, J=9.2 Hz, 2.8 Hz,1H), 7.15 (d, J=2.8 Hz, 2H), 7.01 (d, J=2.8 Hz, 1H), 4.31 (d, J=13.2 Hz,2H), 3.91-3.83 (m, 5H), 3.57 (t, J=5.6 Hz, 2H), 3.49-3.39 (m, 1H),3.16-3.03 (m, 5H), 2.23-1.91 (m, 5H), 1.56-1.43 (m, 4H). MS: m/z 452.2(M+H⁺).

Example 207: Preparation of2-{[2-(1-Fluoro-cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-V-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

Step 1: To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butylester (10.0 g, 50 mmol) in dry THF (100 mL) was added LiHMDS (65 mL, 65mmol, 1 M in THF) dropwise at −78° C. under N₂ atmosphere. The resultingmixture was stirred at −78° C. for 1 hr. Then PhN(OTf)₂ was added intothe reaction mixture, and the mixture was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was quenchedwith H₂O (100 mL) and extracted with EtOAc (50 mL×2). The organic layerswere washed with brine (50 mL×2), dried over Na₂SO₄ and concentrated invacuum to give4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (12.0 g, yield: 73%) as a yellow oil, which was usedfor next step without further purification.

Step 2: To a solution of4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (2.0 g, 6.04 mmol) and 2-methoxypyridin-3-ylboronicacid (1.0 g, 6.6 mmol) in dioxane/H₂O (30 mL+20 mL) were addedPd(dppf)Cl₂ (220 mg, 0.3 mmol) and K₂CO₃ (3.33 g, 24 mmol). Theresulting mixture was stirred at 80° C. under N₂ atmosphere overnight.Then the reaction mixture was poured into H₂O (100 mL) and extractedwith EtOAc (20 mL×3). The extracts were washed with brine (20 mL×3),dried over Na₂SO₄ and concentrated in vacuum to give a residue, whichwas purified by a silica gel column (DCM/MeOH=50/1) to afford2-methoxy-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-F-carboxylic acidtert-butyl ester (1.36 g, yield: 78%) as a yellow oil. MS: m/z 291.0(M+H⁺).

Step 3: To a solution of2-methoxy-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (1.36 g, 4.68 mmol) in MeOH (30 mL) was added wet Pd/C(140 mg, 10% wt). The resulting mixture was stirred at room temperatureunder H₂ atmosphere overnight. Then Pd/C was filtered off and thefiltrate was concentrated in vacuum to afford2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (1.30 g, yield: 95%) as a colorless oil.

Step 4: To a solution of2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (1.30 g, 4.45 mmol) in EtOAc (20 mL) was addedHCl/EtOAc (excess). The resulting mixture was stirred at roomtemperature for 4 hrs. The solid precipitated form the reaction mixturewas collected by filtration. The cake was washed with EtOAc (60 mL),ether (60 mL) and air-dried to afford2-methoxy-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl (950 mg, yield:93%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.28 (brs, 2H), 8.06(dd, J=4.8, 1.2 Hz, 1H), 7.53 (d, J=6.8 Hz, 1H), 7.01 (dd, J=7.2, 5.2Hz, 1H), 3.90 (s, 3H), 3.35-3.29 (m, 2H), 3.11-2.90 (m, 3H), 1.98-1.82(m, 4H).

Step 5: To a mixture of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(100 mg, 0.361 mmol) and2-methoxy-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl (91 mg, 0.397mmol) in MeCN (20 mL) were added BOP (240 mg, 0.542 mmol) and DBU (220mg, 1.44 mmol). The resulting mixture was stirred at room temperatureovernight. Then MeCN was removed in vacuum to give a residue, which waspurified by Prep-HPLC with NH₄OH as additive to afford2-{[2-(1-fluoro-cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol(31.6 mg, yield: 20%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.05(dd, J=5.6, 1.6 Hz, 1H), 7.87 (d, J=9.2 Hz, 1H), 7.46 (dd, J=7.2, 1.2Hz, 1H), 7.39 (dd, J=9.6, 2.4 Hz, 1H), 6.95 (d, J=2.8 Hz, 1H), 6.88 (dd,J=7.6, 1.2 Hz, 1H), 4.34 (d, J=12.8 Hz, 2H), 3.98 (s, 3H), 3.88 (t,J=5.6 Hz, 2H), 3.58 (t, J=5.6 Hz, 2H), 3.19-3.08 (m, 3H), 3.07 (s, 3H),2.03-1.78 (m, 5H), 1.54-1.46 (m, 4H). MS: m/z 452.2 (M+H⁺).

Example 208: Preparation of2-({2-(1-Fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1 To a solution of4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (10.0 g, 30.2 mmol) and bis(pinacolato)diboron (9.2 g,36.2 mmol) in dioxane (250 mL) were added Pd(dppf)Cl₂ (1.1 g, 1.5 mmol),dppf (0.84 g, 1.5 mmol) and KOAc (10.4 g, 106 mmol). The resultingmixture was stirred at 80° C. under N₂ overnight. Then the reactionmixture was poured into H₂O (100 mL) and extracted with EtOAc (50 mL×3).The extracts were washed with brine (50 mL×3), dried over Na₂SO₄ andconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EtOAc=50/1) to afford4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (6.8 g, yield: 73%) as a white solid. ¹H NMR (400MHz, CDCl₃): δ=6.46 (brs, 1H), 4.03-3.89 (m, 2H), 3.50-3.38 (m, 2H),2.28-2.15 (m, 2H), 1.46 (s, 9H), 1.26 (m, 12H).

Step 2: To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.0 g, 3.23 mmol) and 2-chloro-3-methoxy-pyrazine(425 mg, 2.94 mmol) in dioxane/H₂O (30 mL+10 mL) were added Pd(dppf)Cl₂(108 mg, 0.15 mmol) and K₂CO₃ (1.62 g, 11.8 mmol). The resulting mixturewas stirred at 80° C. under N₂ atmosphere overnight. Then the reactionmixture was poured into H₂O (100 mL) and extracted with EtOAc (20 mL×3).The extracts were washed with brine (20 mL×3), dried over Na₂SO₄ andconcentrated in vacuum to give a residue, which was purified by a silicagel column (DCM/MeOH=50/1) to afford4-(3-methoxy-pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (648 mg, yield: 76%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ=8.11 (d, J=2.4 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 6.97-6.71 (m,1H), 4.23-4.10 (m, 2H), 4.00 (s, 3H), 3.70-3.54 (m, 2H), 2.76-2.59 (m,2H), 1.49 (s, 9H).

Step 3: To a solution of4-(3-methoxy-pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (648 mg, 2.22 mmol) in MeOH (20 mL) was added wet Pd/C(65 mg, 10% wt). The resulting mixture was stirred at room temperatureunder H₂ atmosphere overnight. Then Pd/C was filtered off and thefiltrate was concentrated in vacuum to afford4-(3-methoxy-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester(650 mg, yield: 100%) as a colorless oil, which was used for next stepwithout further purification.

Step 4: To a solution of4-(3-methoxy-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester(650 mg, 2.22 mmol) in EtOAc (20 mL) was added HCl/EtOAc (excess). Theresulting mixture was stirred at room temperature for 4 hrs. The solidprecipitated form the reaction mixture was collected by filtration. Thecake was washed with EtOAc (60 mL), ether (60 mL) and air-dried toafford 2-methoxy-3-piperidin-4-yl-pyrazine (500 mg, yield: 98%) as awhite solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.24 (brs, 1H), 9.04 (brs,1H), 8.16 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 3.94 (s, 3H),3.37-3.24 (m, 3H), 3.10-2.96 (m, 2H), 1.98-1.89 (m, 4H).

Step 5: To a mixture of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(100 mg, 0.361 mmol) and 2-methoxy-3-piperidin-4-yl-pyrazine (92 mg,0.397 mmol) in ACN (20 mL) were added BOP (240 mg, 0.542 mmol) and DBU(220 mg, 1.44 mmol). The resulting mixture was stirred at roomtemperature overnight. Then ACN was removed in vacuum to give a residue,which was purified by Prep-HPLC with NH₄OH as additive to afford2-({2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol(36 mg, yield: 22%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.07(d, J=2.8 Hz, 1H), 7.97 (d, J=3.2 Hz, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.39(dd, J=9.6, 2.4 Hz, 1H), 6.97 (d, J=2.8 Hz, 1H), 6.88 (dd, J=87.2, 4.8Hz, 1H), 4.32 (d, J=12.4 Hz, 2H), 4.00 (s, 3H), 3.88 (t, J=5.6 Hz, 2H),3.58 (t, J=5.6 Hz, 2H), 3.38-3.28 (m, 1H), 3.19-3.09 (m, 2H), 3.07 (s,3H), 2.16-1.96 (m, 5H), 1.56-1.46 (m, 4H). MS: m/z 453.2 (M+H⁺).

Example 209: Preparation of2-({2-(1-Fluoro-cyclopropyl)-4-[4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

To a mixture of piperazine-1-carboxylic acid tert-butyl ester (500 mg,2.68 mmol) and 2-bromo-3-methoxy-pyridine (500 mg, 2.68 mmol) in toluene(40 mL) were added Pd₂(dba)₃ (258 mg, 0.268 mmol), BINAP (250 mg, 0.40mmol) and t-BuOK (450 mg, 4.03 mmol). The resulting mixture was stirredat 110° C. under N₂ atmosphere overnight. Then toluene was removed invacuum to give a residue, which was purified by a silica gel column toafford 4-(3-Methoxy-pyridin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester (574 mg, yield: 74.4%) as a yellow oil. ¹H NMR (400MHz, CDCl₃): δ=7.86 (dd, J=4.8, 1.2 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H),6.86 (dd, J=8.0, 4.8 Hz, 1H), 3.86 (s, 3H), 3.58 (t, J=4.8 Hz, 4H), 3.48(t, J=4.8 Hz, 4H), 1.48 (s, 9H).

To a solution of 4-(3-methoxy-pyridin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester (574 mg, 1.96 mmol) in EtOAc (10 mL) was addedHCl/EtOAc (excess). The resulting mixture was stirred at roomtemperature for 4 hrs. Then the solid precipitated form the reactionmixture was filtered. The cake was washed with EtOAc (50 mL) and ether(50 mL) to afford 1-(3-Methoxy-pyridin-2-yl)-piperazine (448 mg, yield:99%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d6): δ=9.64 (brs, 2H),7.79 (dd, J=5.7, 1.2 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.13 (dd, J=7.8,5.4 Hz, 1H), 3.88 (s, 3H), 3.82-3.70 (m, 4H), 3.30-3.11 (m, 4H).

To a mixture of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(100 mg, 0.361 mmol) and 1-(3-methoxy-pyridin-2-yl)-piperazine (92 mg,0.397 mmol) in MeCN (20 mL) were added BOP (240 mg, 0.542 mmol) and DBU(220 mg, 1.44 mmol). The resulting mixture was stirred at roomtemperature overnight. Then MeCN was removed in vacuum to give aresidue, which was purified by Prep-HPLC with NH₄OH as additive toafford2-({2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol(36.7 mg, yield: 22.5%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃):δ=7.90 (dd, J₁=4.8 Hz, J₂=1.6 Hz, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.40 (dd,J₁=9.6, 2.4 Hz, 1H), 7.09 (dd, J=8.0, 1.2 Hz, 1H), 6.98 (d, J=2.4 Hz,1H), 6.90 (dd, J=8.0, 0.8 Hz, 1H), 3.93-3.86 (m, 5H), 3.75 (t, J=4.8 Hz,4H), 3.61-3.55 (m, 6H), 3.07 (s, 3H), 1.56-1.46 (m, 4H). MS: m/z 453.2(M+H⁺).

Example 210: Preparation of2-{[2-(1-Fluoro-cyclopropyl)-4-(4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

Step 1: To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.0 g, 3.23 mmol) and 3-bromo-4-methoxy-pyridine(552 mg, 2.94 mmol) in dioxane/H₂O (30 mL+10 mL) were added Pd(dppf)Cl₂(108 mg, 0.14 mmol) and K₂CO₃ (1.62 g, 11.8 mmol). The resulting mixturewas stirred at 80° C. under N₂ atmosphere overnight. Then the reactionmixture was poured into H₂O (100 mL) and extracted with EtOAc (20 mL×3).The extracts were washed with brine (20 mL×3), dried over Na₂SO₄ andconcentrated in vacuum to give a residue, which was purified by a silicagel column with DCM:MeOH=50:1 as eluent to afford4-methoxy-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (721 mg, yield: 85%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ=8.40 (d, J=5.2 Hz, 1H), 8.27 (s, 1H), 6.79 (d, J=4.8 Hz, 1H),5.81 (s, 1H), 4.12-4.02 (m, 2H), 3.87 (s, 3H), 3.66-3.54 (m, 2H),2.53-2.43 (m, 2H), 1.49 (s, 9H).

Step 2: To a solution of4-methoxy-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (721 mg, 2.48 mmol) in MeOH (20 mL) was added wet Pd/C(72 mg, 10% wt). The resulting mixture was stirred at room temperatureunder H₂ atmosphere overnight. Then Pd/C was filtered off and thefiltrate was concentrated in vacuum to afford4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-F-carboxylic acidtert-butyl ester (352 mg, yield: 48%) as a white solid, which was usedfor next step without further purification.

Step 3: To a solution of4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (352 mg, 12.0 mmol) in EtOAc (20 mL) was addedHCl/EtOAc (excess). The resulting mixture was stirred at roomtemperature for 4 hrs. The solid precipitated form the reaction mixturewas collected by filtration. The cake was washed with EtOAc (60 mL),ether (60 mL) and air-dried to afford4-methoxy-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl (236 mg, yield:86%) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.37 (brs, 2H), 8.80(s, 1H), 8.48 (s, 1H), 7.66 (s, 1H), 4.14 (s, 3H), 3.42-3.30 (m, 2H),3.28-3.15 (m, 1H), 3.10-2.93 (m, 2H), 2.11-1.83 (m, 4H).

Step 4: To a mixture of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(100 mg, 0.361 mmol) and4-methoxy-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl (91 mg, 0.397mmol) in ACN (20 mL) were added BOP (240 mg, 0.542 mmol) and DBU (220mg, 1.44 mmol). The resulting mixture was stirred at room temperatureovernight. Then ACN was removed in vacuum to give a residue, which waspurified by Prep-HPLC with NH₄OH as additive to afford2-{[2-(1-fluoro-cyclopropyl)-4-(4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol(43.2 mg, yield: 27%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.39(d, J=5.2 Hz, 1H), 8.35 (s, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.38 (dd,J=9.6, 3.2 Hz, 1H), 6.95 (d, J=3.2 Hz, 1H), 6.80 (d, J=5.6 Hz, 1H),4.37-4.27 (m, 2H), 3.93-3.85 (m, 5H), 3.59 (t, J=5.6 Hz, 2H), 3.23-3.14(m, 1H), 3.13-3.05 (m, 5H), 2.04-1.92 (m, 5H), 1.55-1.45 (m, 4H). MS:m/z 452.2 (M+H⁺).

Example 211: Preparation of2-({2-(1-Fluoro-cyclopropyl)-4-[4-(5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.0 g, 3.23 mmol) and2,4-dichloro-5-methoxy-pyrimidine (526 mg, 2.94 mmol) in dioxane/H₂O (30mL+10 mL) were added Pd(dppf)Cl₂ (108 mg, 0.14 mmol) and K₂CO₃ (1.62 g,11.8 mmol). The resulting mixture was stirred at 80° C. under N₂atmosphere overnight. Then the reaction mixture was poured into H₂O (100mL) and extracted with EtOAc (20 mL×3). The extracts were washed withbrine (20 mL×3), dried over Na₂SO₄ and concentrated in vacuum to give aresidue, which was purified by a silica gel column (DCM/MeOH=50/1) toafford4-(2-chloro-5-methoxy-pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (900 mg, yield: 94%) as a yellow oil. ¹H NMR (400MHz, CDCl₃): δ=8.20 (s, 1H), 7.08-6.86 (m, 1H), 4.23-4.12 (m, 2H), 3.96(s, 3H), 3.60 (t, J=5.6 Hz, 2H), 2.72-2.61 (m, 2H), 1.49 (s, 9H).

Step 2: To a solution of4-(2-chloro-5-methoxy-pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (900 g, 2.76 mmol) in MeOH (20 mL) was added wetPd/C (90 mg, 10% wt). The resulting mixture was stirred at roomtemperature under H₂ atmosphere overnight. Then Pd/C was filtered offand the filtrate was concentrated in vacuum to afford4-(5-methoxy-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butylester (800 g, yield: 99%) as a white solid, which was used for next stepwithout further purification.

Step 3: To a solution of4-(5-methoxy-pyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butylester (800 mg, 2.73 mmol) in EtOAc (20 mL) was added HCl/EtOAc (excess).The resulting mixture was stirred at room temperature for 4 hrs. Thesolid precipitated form the reaction mixture was collected byfiltration. The cake was washed with EtOAc (60 mL), ether (60 mL) andair-dried to afford 5-methoxy-4-piperidin-4-yl-pyrimidine (620 mg,yield: 99%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.24 (brs,1H), 9.00 (brs, 1H), 8.78 (s, 1H), 8.54 (s, 1H), 3.95 (s, 3H), 3.42-3.26(m, 3H), 3.09-2.95 (m, 2H), 2.04-1.82 (m, 4H).

Step 4: To a mixture of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(100 mg, 0.361 mmol) and 5-methoxy-4-piperidin-4-yl-pyrimidine (92 mg,0.397 mmol) in MeCN (20 mL) were added BOP (240 mg, 0.542 mmol) and DBU(220 mg, 1.44 mmol). The resulting mixture was stirred at roomtemperature overnight. Then MeCN was removed in vacuum to give aresidue, which was purified by Prep-HPLC with NH₄OH as additive toafford2-({2-(1-Fluoro-cyclopropyl)-4-[4-(5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol(36.3 mg, yield: 22%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.80(s, 1H), 8.28 (s, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.38 (dd, J=9.2, 2.8 Hz,1H), 6.97 (d, J=2.8 Hz, 1H), 4.35-4.26 (m, 2H), 3.96 (s, 3H), 3.88 (t,J=5.6 Hz, 2H), 3.58 (t, J=5.6 Hz, 2H), 3.46-3.36 (m, 1H), 3.17-3.05 (m,5H), 2.21-1.91 (m, 5H), 1.56-1.45 (m, 4H). MS: m/z 453.2 (M+H⁺).

Example 212: Preparation of2-{[2-(1-Fluoro-cyclopropyl)-4-(3′-methoxy-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

Step 1: To a solution of 3-methoxy-pyridine (5.0 g, 45.8 mmol) in DCM(100 mL) was added m-CPBA (15.0 g, 68.7 mmol). The resulting mixture wasstirred at room temperature overnight. Then Na₂SO₃ (excess) was addedinto the reaction mixture and the mixture was stirred for 10 mins. Theorganic phase was collected and concentrated to give 3-methoxy-pyridine1-oxide (4.2 g, yield: 73%) as a white solid, which was used for nextstep without further purification. NMR (400 MHz, CDCl₃): δ=7.98 (t,J=2.0 Hz, 1H), 7.93-7.87 (m, 1H), 7.16 (dd, J=8.4, 6.4 Hz, 1H), 6.88 (s,dd, J=8.8, 1.6 Hz, 1H), 3.85 (s, 3H).

Step 2: To a solution of 3-methoxy-pyridine 1-oxide (2.0 g, 16 mmol) insulfuric acid (4 mL) was added fuming nitric acid (4 mL) at 0° C.dropwise. After addition of the nitric acid was completed, the reactionmixture was warmed to room temperature and then heated at 90° C. for 2hrs. Then the reaction mixture was cooled in ice bath and adjusted to pH10 with 2 M aqueous Na₂CO₃. The solution was extracted with DCM (50mL×2). The extracts were collected and concentrated to give a residue,which was purified by a silica gel column (DCM/MeOH=50/1) to afford3-methoxy-4-nitro-pyridine 1-oxide (1.5 g, yield: 55%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ=7.98 (d, J=1.6 Hz, 1H), 7.97-7.85 (m,2H), 4.03 (s, 3H).

Step 3: To a solution of 3-methoxy-4-nitro-pyridine 1-oxide (3.0 g, 17.6mmol) in acetic AcOH (30 mL) was added AcBr (65.0 g, 529 mmol). Theresulting mixture was stirred at 80° C. for 1 hr. Then the reactionmixture was neutralized with saturated aqueous NaOH till pH=8. Theaqueous phase was extracted with EtOAc (60 mL×4). The extracts werewashed with brine (60 mL×4), dried over Na₂SO₄ and concentrated toafford 4-bromo-3-methoxy-pyridine 1-oxide (3.2 g, yield: 89%) as ayellow solid, which was used for next step without further purification.MS: m/z 203.9 (M+H⁺).

Step 4: To a solution of 4-bromo-3-methoxy-pyridine 1-oxide (1.0 g, 4.90mmol) and4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (1.82 g, 5.88 mmol) in dioxane/H₂O (30 mL+10 mL)were added Pd(dppf)Cl₂ (180 mg, 0.245 mmol) and K₂CO₃ (2.70 g, 19.6mmol). The resulting mixture was stirred at 80° C. under N₂ atmosphereovernight. Then the reaction mixture was poured into H₂O (100 mL) andextracted with EtOAc (20 mL×3). The extracts were washed with brine (20mL×3), dried over Na₂SO₄ and concentrated in vacuum to give a residue,which was purified by a silica gel column with DCM/MeOH=50/1 as eluentto afford3′-methoxy-1′-oxy-3,6-dihydro-2H-[4,4′]bipyridinyl-1-carboxylic acidtert-butyl ester (1.1 g, yield: 73%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ=7.93 (d, J=1.6 Hz, 1H), 7.87 (dd, J=6.4, 1.6 Hz, 1H), 7.02 (d,J=6.8 Hz, 1H), 6.06 (brs, 1H), 4.13-4.02 (m, 2H), 3.87 (s, 3H), 3.60 (t,J=5.6 Hz, 2H), 2.54-2.39 (m, 2H), 1.49 (s, 9H).

Step 5: To a solution of3′-methoxy-1′-oxy-3,6-dihydro-2H[4,4′]bipyridinyl-1-carboxylic acidtert-butyl ester (1.1 g, 3.59 mmol) in MeOH (30 mL) was added wet Pd/C(110 mg, 10% wt). The resulting mixture was stirred at room temperatureunder H₂ atmosphere overnight. Then Pd/C was filtered off and thefiltrate was concentrated in vacuum to afford3′-methoxy-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylic acidtert-butyl ester (950 mg, yield: 90.5%) as a green solid, which was usedfor next step without further purification.

Step 6: To a solution of3′-methoxy-3,4,5,6-tetrahydro-2H[4,4′]bipyridinyl-1-carboxylic acidtert-butyl ester (950 mg, 3.25 mmol) in MeOH (10 mL) was added HCl/EtOAc(excess). The resulting mixture was stirred at room temperature for 4hrs. The solid precipitated form the reaction mixture was collected byfiltration. The cake was washed with EtOAc (60 mL), ether (60 mL) andair-dried to afford 3′-methoxy-1,2,3,4,5,6-hexahydro[4,4′]bipyridinyl(560 mg, yield: 75%) as a grey solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.30(brs, 1H), 9.22 (brs, 1H), 8.62 (s, 1H), 8.53 (d, J=5.6 Hz, 1H), 7.75(d, J=5.6 Hz, 1H), 4.04 (s, 3H), 3.41-3.29 (m, 3H), 3.11-2.94 (m, 2H),2.03-1.84 (m, 4H).

Step 7: To a mixture of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(100 mg, 0.361 mmol) and3′-methoxy-1,2,3,4,5,6-hexahydro[4,4′]bipyridinyl (92 mg, 0.397 mmol) inMeCN (20 mL) were added BOP (240 mg, 0.542 mmol) and DBU (220 mg, 1.44mmol). The resulting mixture was stirred at room temperature overnight.Then MeCN was removed in vacuum to give a residue, which was purified byPrep-HPLC with NH₄OH as additive to afford2-{[2-(1-Fluoro-cyclopropyl)-4-(3′-methoxy-3,4,5,6-tetrahydro-2H[4,4′]bipyridinyl-1-yl)-quinazolin-6-yl]-methyl-amino}-ethanol(33.2 mg, yield: 21%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.24(s, 2H), 7.87 (d, J=9.2 Hz, 1H), 7.40 (dd, J=9.6, 2.8 Hz, 1H), 7.14 (d,J=4.8 Hz, 1H), 6.95 (d, J=3.2 Hz, 1H), 4.38-4.29 (m, 2H), 3.95 (s, 3H),3.89 (t, J=5.2 Hz, 2H), 3.58 (t, J=5.6 Hz, 2H), 3.31-3.19 (m, 1H),3.18-3.08 (m, 2H), 3.07 (s, 3H), 2.04-1.80 (m, 5H), 1.55-1.46 (m, 4H).MS: m/z 452.2 (M+H⁺).

Example 213: Preparation of2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: To a solution of 1-fluoro-cyclopropanecarboxylic acid (434 mg,4.17 mmol) in dry DCM (10 mL) was added (COCl)₂ (644 mg, 5.0 mmol) and 2drops of dry DMF. The resulting mixture was stirred at room temperaturefor 2 hrs. Then the mixture was added to a solution of2-amino-3-fluoro-benzonitrile (900 mg, 4.17 mmol) in DCM (10 mL). Thereaction mixture was stirred at room temperature for another 2 hrs. Thenthe mixture was washed with H₂O (100 mL), 1 N HCl (100 mL) and saturatedNaHCO₃ (50 mL×2). The organic phase was concentrated to give a residue,which was purified by silica gel column with DCM as eluent to afford1-fluoro-cyclopropanecarboxylic acid(4-bromo-2-cyano-6-fluoro-phenyl)-amide (1.08 g, yield: 85%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ=8.02 (brs, 1H), 7.65 (s, 1H), 7.60(dd, J=8.8, 2.4 Hz, 1H), 1.61-1.43 (m, 4H).

Step 2: To a solution of 1-fluoro-cyclopropanecarboxylic acid(4-bromo-2-cyano-6-fluoro-phenyl)-amide (1.08 g, 3.58 mmol) in EtOH (30mL) was added H₂O₂ (10 mL, 30% in H₂O) and NaOH (172 mg, 4.3 mmol). Theresulting mixture was stirred at 85° C. overnight. Then the reactionmixture was concentrated to give only 10 mL suspension. The resultingsolid was collected by filtration to afford6-bromo-8-fluoro-2-(1-fluoro-cyclopropyl)-quinazolin-4-ol (702 mg,yield: 65%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=12.92 (brs,1H), 8.04-7.98 (m, 2H), 1.66-1.46 (m, 4H).

Step 3: To a mixture of6-bromo-8-fluoro-2-(1-fluoro-cyclopropyl)-quinazolin-4-ol (2.17 g, 7.21mmol) and 2-amino-ethanol (0.66 mg, 10.8 mmol) in DMSO (20 mL) was addedCuI (137 mg, 0.721 mmol), L-proline (166 mg, 1.44 mmol) and K₃PO₄ (3.06g, 14.4 mmol). The resulting mixture was stirred at 100° C. under N₂atmosphere overnight. Then DMSO was removed in vacuum to give a crudeproduct8-fluoro-2-(1-fluoro-cyclopropyl)-6-(2-hydroxy-ethylamino)-quinazolin-4-ol(4.0 g), which was used for next step without further purification. MS:m/z 281.9 (M+H⁺).

Step 4: To a solution of8-fluoro-2-(1-fluoro-cyclopropyl)-6-(2-hydroxy-ethylamino)-quinazolin-4-ol(4.0 g, crude) in MeOH (100 mL) was added formaldehyde (20 mL, 37% inH₂O). The resulting mixture was stirred at room temperature for 2 hrs.Then NaBH(OAc)₃ (12.1 g, 56.8 mmol) and NaBH₃CN (3.58 g, 56.8 mmol) wasadded into the reaction mixture. The reaction mixture was stirred atroom temperature overnight. Then the mixture was poured into water (100mL) and extracted with EtOAc (60 mL×3). The organic layers wereconcentrated in vacuum to give a residue, which was purified by a silicagel column (DCM/MeOH=20/1) to afford8-fluoro-2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(1.85 g, two-step yield: 87%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d6): δ=12.38 (brs, 1H), 7.16 (dd, J=14.4, 2.8 Hz, 1H), 7.00 (d,J=2.4 Hz, 1H), 4.75 (brs, 1H), 3.58 (t, J=5.6 Hz, 2H), 3.48 (t, J=5.6Hz, 2H), 3.01 (s, 3H), 1.55-1.37 (m, 4H). MS: m/z 295.9 (M+H⁺).

Step 5: To a mixture of8-fluoro-2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(150 mg, 0.508 mmol) and 2-methoxy-3-piperidin-4-yl-pyrazine (128 mg,0.558 mmol) in MeCN (20 mL) was added BOP (336 mg, 0.762 mmol) and DBU(309 mg, 2.03 mmol). The resulting mixture was stirred at roomtemperature overnight. Then MeCN was removed in vacuum to give aresidue, which was purified by Prep-HPLC with NH₄OH as additive toafford2-({8-fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol(76 mg, yield: 32%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.07(d, J=2.8 Hz, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.08 (dd, J=12.8, 2.8 Hz,1H), 6.72 (d, J=2.0 Hz, 1H), 4.32 (d, J=13.2 Hz, 2H), 4.00 (s, 3H), 3.88(t, J=5.6 Hz, 2H), 3.55 (t, J=5.6 Hz, 2H), 3.39-3.28 (m, 1H), 3.20-3.10(m, 2H), 3.05 (s, 3H), 2.14-1.98 (m, 5H), 1.56-1.45 (m, 4H). MS: m/z471.1 (M+H⁺).

Example 214: Preparation of2-{[8-Fluoro-2-(1-fluoro-cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described in example2-({8-fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.05 (dd, J=5.2, 1.6 Hz, 1H), 7.45 (dd,J=7.2, 1.6 Hz, 1H), 7.11 (dd, J=13.6, 2.4 Hz, 1H), 6.88 (dd, J=7.2, 4.8Hz, 1H), 6.74 (s, 1H), 4.37 (d, J=12.8 Hz, 2H), 3.98 (s, 3H), 3.88 (t,J=5.6 Hz, 2H), 3.56 (t, J=5.6 Hz, 2H), 3.20-3.11 (m, 3H), 3.06 (s, 3H),2.03-1.96 (m, 2H), 1.90-1.77 (m, 3H), 1.55-1.47 (m, 4H). MS: m/z 470.1(M+H⁺).

Example 215: Preparation of2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described in example2-({8-fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=7.90 (d, J=4.0 Hz, 1H), 7.14-7.06 (m, 2H),6.89 (dd, J=8.0, 4.8 Hz, 1H), 6.75 (s, 1H), 3.92-3.86 (m, 5H), 3.80-3.74(m, 4H), 3.61-3.54 (m, 6H), 3.06 (s, 3H), 2.05-1.97 (m, 1H, activeproton), 1.57-1.47 (m, 4H). MS: m/z 471.1 (M+H⁺).

Example 216: Preparation of2-{[8-Fluoro-2-(1-fluoro-cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

The title compound was prepared as described in example2-({8-fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.16 (t, J=3.2 Hz, 1H), 7.18-7.14 (m, 2H),7.08 (dd, J=13.2, 2.8 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 4.33 (d, J=13.6Hz, 2H), 3.91-3.84 (m, 5H), 3.55 (t, J=5.6 Hz, 2H), 3.51-3.40 (m, 1H),3.17-3.07 (m, 2H), 3.06 (s, 3H), 2.22-1.93 (m, 5H), 1.56-1.43 (m, 4H).MS: m/z 470.1 (M+H⁺).

Example 217: Preparation of2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

The title compound was prepared as described in example2-({8-fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.¹H NMR (400 MHz, CDCl₃): δ=8.80 (s, 1H), 8.28 (s, 1H), 7.07 (dd, J=13.2,1.6 Hz, 1H), 6.72 (s, 1H), 4.32 (d, J=13.2 Hz, 2H), 3.96 (s, 3H),3.92-3.84 (m, 2H), 3.56 (t, J=5.6 Hz, 2H), 3.48-3.36 (m, 1H), 3.13 (t,J=12.0 Hz, 2H), 3.06 (s, 3H), 2.28-1.91 (m, 5H), 1.56-1.43 (m, 4H). MS:m/z 470.9 (M+H⁺).

Example 218: Preparation of2-({2-(1-Fluoro-cyclopropyl)-4-[4-(4-iodo-2-methoxy-phenyl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (7.34 g, 23.7 mmol) and1-bromo-2-methoxy-4-nitro-benzene (5.0 g, 21.5 mmol) in dioxane/H₂O (240mL+80 mL) were added Pd(dppf)Cl₂ (788 mg, 1.1 mmol) and K₂CO₃ (11.9 g,86.2 mmol). The resulting mixture was stirred at 80° C. under N₂atmosphere overnight. Then the reaction mixture was poured into H₂O (200mL) and the aqueous phase was extracted with EtOAc (80 mL×2). Theextracts were washed with brine (20 mL×3), dried over Na₂SO₄ andconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EtOAc=10/1) to afford4-(2-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (7.1 g, yield: 98%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃): δ=7.82 (dd, J=8.0, 2.4 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.28 (d,J=8.4 Hz, 1H), 5.87 (brs, 1H), 4.10-4.06 (m, 2H), 3.92 (s, 3H), 3.61 (t,J=5.6 Hz, 2H), 2.52-2.47 (s, 2H), 1.50 (s, 9H).

Step 2: To a solution of4-(2-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (7.1 g, 21.2 mmol) in MeOH (200 mL) was added wet Pd/C(710 mg, 10% wt). The resulting mixture was stirred at room temperatureunder H₂ atmosphere (50 psi) overnight. Then Pd/C was filtered off andthe filtrate was concentrated in vacuum to afford4-(4-amino-2-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butylester (6.5 g, yield: 100%) as a white solid, which was used for nextstep without further purification. ¹H NMR (400 MHz, CDCl₃): δ=6.90 (d,J=8.4 Hz, 1H), 6.31-6.21 (m, 2H), 4.19 (brs, 2H), 3.77 (s, 3H),3.65-3.55 (m, 2H), 2.99-2.89 (m, 1H), 2.87-2.72 (m, 2H), 1.78-1.69 (m,2H), 1.58-1.49 (m, 2H), 1.48 (s, 9H).

Step 3: To a solution of4-(4-amino-2-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butylester (2.0 g, 6.53 mmol) in MeCN (50 mL) were added CuI (1.86 g, 9.8mmol), CH₂I₂ (8.74 g, 32.6 mmol) and t-butyl nitrite (2.02 g, 19.6 mmol)at 0° C. The resulting mixture was stirred at 0° C. for 1 hr and thenheated at at 80° C. for another 3 hrs. Later, MeCN was removed in vacuumto give a residue, which was purified by a silica gel column(PE/EtOAc=10/1) to afford4-(4-iodo-2-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butylester (805 mg, yield: 30%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃):δ=7.26 (dd, J=8.4, 1.6 Hz, 1H), 7.10 (d, J=1.6 Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 4.37-4.08 (m, 2H), 3.81 (s, 3H), 3.07-2.96 (m, 1H), 2.90-2.70(m, 2H), 1.81-1.68 (m, 2H), 1.56-1.49 (m, 2H), 1.48 (s, 9H).

Step 4: To a solution of4-(4-iodo-2-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butylester (800 mg, 1.92 mmol) in EtOAc (10 mL) was added HCl/EtOAc (excess).The resulting mixture was stirred at room temperature for 4 hrs. Thesolid precipitated form the reaction mixture was collected byfiltration. The cake was washed with EtOAc (60 mL), ether (60 mL) andair-dried to afford 4-(4-iodo-2-methoxy-phenyl)-piperidine (586 mg,yield: 86%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.03 (brs,2H), 7.32 (d, J=7.6 Hz, 1H), 7.29 (s, 1H), 6.91 (d, J=7.6 Hz, 1H), 3.80(s, 3H), 3.38-3.26 (m, 2H), 3.17-3.05 (m, 1H), 3.04-2.91 (m, 2H),1.89-1.76 (m, 4H).

Step 5: To a mixture of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(250 mg, 0.902 mmol) and 4-(4-iodo-2-methoxy-phenyl)-piperidine (351 mg,0.992 mmol) in MeCN (50 mL) were added BOP (600 mg, 1.35 mmol) and DBU(548 mg, 3.61 mmol). The resulting mixture was stirred at roomtemperature overnight. Then MeCN was removed in vacuum to give aresidue, which was purified by Prep-HPLC with NH₄OH as additive toafford2-{[2-(1-fluoro-cyclopropyl)-4-(4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol(278 mg, yield: 54%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=7.90(d, J=9.2 Hz, 1H), 7.40 (dd, J=9.2, 2.8 Hz, 1H), 7.29 (dd, J=8.0, 1.6Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 6.97-6.91 (m, 2H), 4.34 (d, J=13.6 Hz,2H), 3.88 (t, J=5.6 Hz, 2H), 3.83 (s, 3H), 3.58 (t, J=5.6 Hz, 2H),3.25-3.17 (m, 1H), 3.16-3.08 (m, 2H), 3.06 (s, 3H), 1.96-1.78 (m, 5H),1.54-1.47 (m, 4H). MS: m/z 577.1 (M+H⁺).

Example 219: Preparation of2-({2-(1-Fluoromethyl-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

Step 1: The procedure is similar to step 2 of2-{[8-fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol.

Step 2: To a solution of 1-bromo-cyclobutanecarboxylic acid(4-bromo-2-cyano-phenyl)-amide (3 g, 8.4 mmol) in DMF (50 mL) was addedAcONa (1.38 g, 16.8 mmol), and the mixture was then stirred at 90° C.overnight. Resultant was quenched with water (200 mL). The aqueous phasewas extracted with EtOAc (100 mL×2). The organic layer was concentratedand purified by flash column (EtOAc in PE: 0 to 50%) to afford aceticacid 1-(4-bromo-2-cyano-phenylcarbamoyl)-cyclobutyl ester (1.6 g, yield:57%) as a white solid.

Step 3: To a solution of acetic acid1-(4-bromo-2-cyano-phenylcarbamoyl)-cyclobutyl ester (1.6 g, 4.76 mmol)in THF/H₂O (5/1, 60 mL) was added LiOH (1.3 g, 23.8 mmol), it was thenstirred at room temperature overnight. Resultant was evaporated toremove THF and the residue was diluted with water (100 mL). The mixturewas acidified to pH to 2 with con. HCl and extracted with EA (100 mL×2).The extracts were dried over Na₂SO₄ and the solution was concentrated toafford 1-hydroxy-cyclobutanecarboxylic acid(4-bromo-2-cyano-phenyl)-amide (1.1 g, yield: 78%) as a white solid.

Step 4: The procedure is similar to step 3 of2-{[8-fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol.

Step 5: To a solution of6-bromo-2-(1-hydroxy-cyclobutyl)-quinazolin-4-ol (500 mg, 1.7 mmol) inDCM (50 mL) was added DAST (355 mg, 2.21 mmol), and the mixture was thenstirred at room temperature for 1 h. Resultant was diluted with water(50 mL) the pH value was adjusted 8 with NaHCO₃. The organic layer wasseparated and concentrated to dryness. The residue was purified by flashcolumn (C₁₈-silica; MeCN in water: 5% to 95%; 40 min) to afford6-bromo-2-(1-fluoromethyl-cyclopropyl)-quinazolin-4-ol (280 mg, yield:56%) as a pale solid.

Step 6: The procedure is similar to step 4 of2-{[8-fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol.

Step 7: The procedure is similar to step 4 of2-({2-Cyclopropylethynyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.

Step 8: The procedure is similar to step 5 of2-{[8-fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanoland the target was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d6):δ=8.15 (d, J=3.2 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.60 (d, J=9.2 Hz,1H), 7.44 (dd, J=9.2, 2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 4.90 (d,J=48.4 Hz, 2H), 4.72 (t, J=4.8 Hz, 1H), 4.29-4.26 (m, 2H), 3.95 (s, 3H),3.60-3.57 (m, 2H), 3.50-3.47 (m, 2H), 3.17-3.14 (m, 2H), 3.02 (s, 3H),1.94-1.93 (m, 4H), 1.38-1.37 (m, 2H), 1.06-1.03 (m, 2H). MS: m/z 467.2(M+H⁺).

Example 220: Preparation of2-({2-(1-Fluoro-cyclobutyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanoland Example 221: Preparation of1-(6-((2-hydroxyethyl)(methyl)amino)-4-(4-(3-methoxypyrazin-2-yl)piperidin-1-yl)quinazolin-2-yl)cyclobutanol

Step 1: The procedure is similar to step 2 of2-{[8-fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol.

Step 2: To a solution of 1-fluoro-cyclobutanecarboxylic acid(4-bromo-2-cyano-phenyl)-amide (1.5 g, 5.07 mmol) in EtOH (50 mL) wasadded H₂O₂(10 mL) and then NaOH (406 mg, 10.14 mmol), the mixture wasthen heated at reflux for 2 h. Resultant was cooled to room temperatureand evaporated to remove EtOH. The residue was diluted with water (100mL). The aqueous phase was acidified to 2 with con. HCl, and thenextracted with EtOAc (100 mL×2). The organic layer was concentrated andthe residue was purified by flash column (C₁₈-silica; MeCN in water: 5%to 95%; 40 min) to afford6-bromo-2-(1-fluoro-cyclobutyl)-quinazolin-4-ol (1.1 g, yield: 73%)along with minor amount of6-bromo-2-(1-hydroxy-cyclobutyl)-quinazolin-4-ol as a pale solid.

Step 3-4: The procedure is similar to step 3 and 4 of2-({2-(1-fluoromethyl-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol.

Step 5: To a solution of2-(1-fluoro-cyclobutyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(100 mg, 0.34 mmol) in MeCN (50 mL) was added2-methoxy-3-piperidin-4-yl-pyrazine (79 mg, 0.44 mmol), BOP (225 mg,0.51 mmol) and DBU (0.2 mL), it was then stirred at room temperatureovernight. Resultant was concentrated to dryness and the residue waspurified directly by prep-HPLC to afford2-({2-(1-fluoro-cyclobutyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol(30 mg, yield: 18%) and1-{6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-2-yl}-cyclobutanol(10 mg, yield: 6%) as yellow solids.2-({2-(1-Fluoro-cyclobutyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol:¹H NMR (400 MHz, CD₃OD): δ=8.06 (d, J=2.4 Hz, 1H), 8.02 (d, J=3.2 Hz,1H), 7.77 (d, J=9.2 Hz, 1H), 7.55 (dd, J=9.2, 2.8 Hz, 1H), 7.04 (d,J=2.4 Hz, 1H), 4.71-4.68 (m, 2H), 4.01 (s, 3H), 3.79 (t, J=6.0 Hz, 2H),3.62 (t, J=5.6 Hz, 2H), 3.51-3.42 (m, 3H), 3.13 (s, 3H), 2.89-2.82 (m,2H), 2.68-2.63 (m, 2H), 2.13-2.00 (m, 6H). MS: m/z 467.2 (M+H⁺).

1-{6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-2-yl}-cyclobutanol:¹H NMR (400 MHz, CD₃OD): δ=8.04 (d, J=2.8 Hz, 1H), 8.00 (d, J=2.8 Hz,1H), 7.73 (d, J=9.2 Hz, 1H), 7.48 (dd, J=9.2, 2.4 Hz, 1H), 6.97 (d,J=2.4 Hz, 1H), 4.49-4.46 (m, 2H), 4.00 (s, 3H), 3.77 (t, J=6.0 Hz, 2H),3.58 (t, J=6.0 Hz, 2H), 3.43-3.39 (m, 1H), 3.27-3.21 (m, 2H), 3.10 (s,3H), 2.74-2.68 (m, 2H), 2.42-2.35 (m, 2H), 2.13-1.93 (m, 7H). MS: m/z465.2 (M+H⁺).

Example 222: Preparation of(2-(1-Fluoro-cyclopropyl)-4-{4-[2-(2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine

Step 1: To a solution of 4-(2-methoxy-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (2.6 g, 8.9 mmol) in DCM (35 mL), was added BBr₃(2.45 g, 9.8 mmol) slowly at −78° C. under N₂. The reaction was stirredat room temperature over weekend before quenched with NH₄OH. The mixturewas separated between DCM (25 mL) and water (60 mL). The organic layerwas dried over Na₂SO₄, concentrated to give 2-piperidin-4-yl-phenol (1g, yield: 63%) as a white solid. ¹H NMR (400 HMz, DMSO-d6): δ=9.30 (brs,1H), 7.09-7.04 (m, 1H), 6.99-6.95 (m, 1H), 6.80-6.72 (m, 2H), 3.72-3.69(m, 1H), 3.08-3.06 (m, 1H), 2.95-2.93 (m, 1H), 2.85-2.83 (m, 1H),2.68-2.63 (m, 1H), 1.72-1.50 (m, 4H).

Step 2: To a suspension of2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-ol(1 g, 3.61 mmol) and BOP (2.39 g, 5.41 mmol) in MeCN (30 mL) was addedDBU (2.2 g, 14.44 mmol) and the mixture was stirred for 30 min. To thereaction, 2-piperidin-4-yl-phenol (639 mg, 3.61 mmol) was added. Thereaction was stirred at room temperature overnight. The mixture wasconcentrated to dryness. The residue was taken up with water (60 mL) andthe aqueous phase was extracted with EtOAc (60 mL). The organic layerwas washed with brine (60 mL), dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column (DCM/EA=1/1) to give2-(1-{2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino}-quinazolin-4-yl]-piperidin-4-yl)-phenol(650 mg, yield: 41%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6):δ=9.40 (s, 1H), 7.79-7.76 (m, 1H), 7.55-7.53 (m, 1H), 7.13 (d, J=7.6 Hz,1H), 7.04-7.00 (m, 1H), 6.91 (s, 1H), 6.81 (d, J=6.8 Hz, 1H), 6.75 (t,J=7.6 Hz, 1H), 4.59-4.58 (m, 1H), 4.57-4.53 (m, 2H), 3.61-3.60 (m, 2H),3.54-3.52 (m, 2H), 3.26-3.21 (m, 3H), 3.05 (s, 3H), 1.98-1.80 (m, 4H),1.66-1.53 (m, 4H). MS: m/z 437.2 (M+H⁺).

Step 3: To a solution of 2-fluoro-ethanol (3.2 g, 50 mmol) in DCM (60mL), was added Tf₂O (15.5 g, 55 mmol) dropwise at −78° C. under N₂. Thereaction was stirred at 10-20° C. for 1 h. The reaction solution wasthen washed with water (80 mL), saturated NaHCO₃ solution (60 mL) andbrine (60 mL), then dried over Na₂SO₄ and concentrated to givetrifluoro-methanesulfonic acid 2-fluoro-ethyl ester (7.9 g, yield: 81%)as a brown oil.

To a solution of2-(1-{2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-yl}-piperidin-4-yl)-phenol(87 mg, 0.2 mmol) in THF (3 mL), was added 2N NaHMDS in THF (0.22 mL,0.44 mmol) at −10° C. with stirring. After 15 min,trifluoro-methanesulfonic acid 2-fluoro-ethyl ester (98 mg, 0.5 mmol)was added at −10° C. The reaction was stirred at room temperature for 1h. The reaction was separated between EtOAc (50 mL) and water (50 mL).The organic layer was dried over Na₂SO₄ and concentrated to dryness invacuum. The residue was purified by prep-TLC (PE/EtOAc=1/1) to give(2-(1-fluoro-cyclopropyl)-4-{4-[2-(2-fluoro-ethoxy)-phenyl}-piperidin-1-yl]-quinazolin-6-yl)-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine(42 mg, yield: 40%) as a yellow solid. NMR (400 MHz, CDCl₃): δ=8.06-8.00(m, 1H), 7.36 (dd, J=9.2, 2.8 Hz, 1H), 7.26-7.20 (m, 2H), 7.00 (t, J=7.6Hz, 1H), 6.90-6.86 (m, 2H), 4.84 (t, J=4 Hz, 1H), 4.72 (t, J=4 Hz, 1H),4.57 (t, J=4 Hz, 1H), 4.45-4.41 (m, 3H), 4.29 (t, J=4 Hz, 1H), 4.23-4.21(m, 1H), 3.74-3.63 (m, 6H), 3.35-3.29 (m, 1H), 3.20-3.14 (m, 2H), 3.08(s, 3H), 2.01-1.90 (m, 4H), 1.55-1.51 (m, 4H). MS: m/z 528.9 (M+H⁺).

Example 223: Preparation of{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine

To a solution of2-({2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol(225 mg, 0.5 mmol) in THF (3 mL), was added 2N NaHMDS in THF (0.3 mL,0.6 mmol) at −10° C. with stirring. After 15 min,trifluoro-methanesulfonic acid 2-fluoro-ethyl ester (147 mg, 0.75 mmol)was added at −10° C. The reaction was stirred at room temperature for 1h. The reaction was separated between EtOAc (50 mL) and water (50 mL).The organic layer was dried over Na₂SO₄ and concentrated to dryness invacuum. The residue was purified by prep-TLC (PE/EtOAc=1/1) to give{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine(65 mg, yield: 52%) as a yellow solid. 1H NMR (400 MHz, CDCl₃):δ=8.10-8.06 (m, 1H), 7.37-7.35 (m, 1H), 7.26-7.21 (m, 2H), 6.98-6.89 (m,3H), 4.5-4.55 (m, 1H), 4.44-4.42 (m, 3H), 3.86 (s, 3H), 3.72-3.65 (m,6H), 3.33-3.28 (m, 1H), 3.21-3.15 (m, 2H), 3.08 (s, 3H), 2.00-1.85 (m,4H), 1.55-1.49 (m, 4H). MS: m/z 496.9 (M+H⁺).

Example 224: Preparation of2-{1-[6-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-(1-fluoro-cyclopropyl)-quinazolin-4-yl]-piperidin-4-yl}-phenol

To a solution of2-(1-{2-(1-fluoro-cyclopropyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-yl}-piperidin-4-yl)-phenol(300 mg, 0.69 mmol) and pyridine (108 mg, 1.38 mmol) in THF (10 mL), wasadded TBSOTf (200 mg, 0.76 mmol) at −10° C. with stirring. After 10 min,the reaction was separated between EtOAc (50 mL) and water (70 mL). Theorganic layer was dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column (PE/EtOAc=2/1) to give2-{1-[6-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-(1-fluoro-cyclopropyl)-quinazolin-4-yl]-piperidin-4-yl}-phenol(350 mg, yield: 92%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6):δ=9.35 (s, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.48 (dd, J=9.2, 2.8 Hz, 1H),7.14-7.12 (m, 1H), 7.03-6.99 (m, 1H), 6.85-6.73 (m, 3H), 4.33-4.30 (m,2H), 3.80-3.77 (m, 2H), 3.60-3.57 (m, 2H), 3.21-3.08 (m, 3H), 3.04 (s,3H), 1.98-1.80 (m, 4H), 1.47-1.40 (m, 4H), 0.78 (s, 9H), 0.00 (s, 6H).MS: m/z 551.2 (M+H⁺).

Example 225: Preparation of2-[(2-(1-Fluoro-cyclopropyl)-4-{4-[2-(2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)-methyl-amino]-ethanol

To a solution of2-{1-[6-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-(1-fluoro-cyclopropyl)-quinazolin-4-yl]-piperidin-4-yl}-phenol(80 mg, 0.145 mmol) in THF (2 mL) was added 2N NaHMDS in THF (0.11 mL,0.22 mmol) at −10° C. with stirring. After 10 min,trifluoro-methanesulfonic acid 2-fluoro-ethyl ester (31 mg, 0.16 mmol)was added at −10° C. The reaction was stirred at room temperature for 10min. 2N HCl (2 mL) was added to the reaction and stirred for 10 min. Themixture was then separated between EA (40 mL) and saturated NaHCO₃solution (40 mL). The organic layer was washed with brine (40 mL), driedover Na₂SO₄ and concentrated to dryness in vacuum. The residue waspurified by prep-TLC (EtOAc) to give2-[(2-(1-fluoro-cyclopropyl)-4-{4-[2-(2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)-methyl-amino]-ethanol(48 mg, yield: 69%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.10(d, J=8.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.26-7.20 (m, 2H), 7.01-6.97(m, 2H), 6.87 (d, J=7.6 Hz, 1H), 4.84-4.83 (m, 1H), 4.72-4.71 (m, 1H),4.48-4.44 (m, 2H), 4.30-4.29 (m, 1H), 4.22-4.21 (m, 1H), 3.89-3.87 (m,2H), 3.60-3.57 (m, 2H), 3.32-3.16 (m, 3H), 3.07 (s, 3H), 2.04- 1.89 (m,4H), 1.57-1.51 (m, 4H). MS: m/z 483.2 (M+H⁺).

PHARMACEUTICAL COMPOSITION EXAMPLES Example A1: Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII),or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is dissolved in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 withMSA, q.s. to at least 20 mg/mL. The mixture is incorporated into adosage unit form suitable for administration by injection.

Example A2: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII),or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomerthereof, is mixed with 750 mg of starch. The mixture is incorporatedinto an oral dosage unit for, such as a hard gelatin capsule, which issuitable for oral administration.

BIOLOGY EXAMPLES

The cell lines utilized in the high-content imaging assays, whichinclude the NTR1-, NTR2-, and GPR35-U2OS osteosarcomas, were obtainedfrom the laboratory of Dr. Lawrence Barak at the Duke University MedicalCenter. The media used in the culture of the cell lines, as well as theassays themselves, consisted of Minimum Essential Medium (15-010-CM) andL-glutamine (25-005-CL) from Cellgro/Mediatech (Manassas, Va.), fetalbovine serum (SH30396.03) from Hyclone (Logan, Utah),penicillin-streptomycin solution (PS-20) from Omega Scientific inTarzana, Calif., G418 (ant-gn-1) from Invivogen (San Diego, Calif.), andzeocin (R250-01) from Invitrogen (Carlsbad, Calif.). Cell lines werecultured in T225 tissue culture flasks (431082) supplied by Corning(Corning, N.Y.). Additional reagents employed include Dulbecco'sPhosphate-Buffered Saline (DPBS) (21-031CV) from Cellgro/Mediatech,Trypsin-EDTA 0.05% (25300) from Invitrogen, paraformaldehyde (30528954)from Acros Organics (Geel, Belgium), Hoechst 33342 (H3570) fromInvitrogen. The high-content assays were run in 1536-well plates (29326)supplied by Aurora Biotechnology (Poway, Calif.) and utilized aluminumplate seals (T592100) from E&K Scientific (Santa Clara, Calif.).

The neurotensin 1 peptide (N6383) from Sigma-Aldrich (St. Louis, Mo.)was used as a positive control in the NTR1 primary HCS assay. For theNTR2 selectivity assay, the non-specific, small molecule3-(4-fluorophenyl)-7,8-dimethoxy-5-(4-methylbenzyl)-5H-pyrazolo[4,3-c]quinolonewhich was synthesized internally was used as a positive control. TheGPR35 selectivity screen utilized zaprinast (ALX430-020-M010) fromAlexis Biochemicals (Farmingdale, N.Y.) as a control.

The NTR1 β-Arrestin assays were performed using a PathHunter™ eXpresskit (93-0446E2) which contained the NTSR1 (NTR1) CHO cell line, OCC2media (30-409), as well as the PathHunter Detection Reagents(93-0446E2). The kit was obtained from DiscoveRx (Fremont, Calif.). Theassay employed the same neurotensin 1 peptide as a control as was usedin the NTR1 primary assay. The assay was run in 1536-well, white,solid-bottom tissue culture plates (3727) from Corning.

The NTR1 Ca²⁺ Flux assay was performed by ChanTest (Rockville, Md.). Theassay used a CHO cell line, provided by ChanTest, which stably expressedthe NTR1 receptor. The cells were grown and plated in Ham's F12 (11765)that was supplemented with fetal bovine serum (10437). Both weresupplied by Gibco/Life Technologies (Carlsbad, Calif.). The DPBS(21-031CV) used in the assay was obtained from Cellgro/Mediatech and theG418 (ant-gn-1) was supplied by Invivogen. The Fluo-4 NW Dye (InvitrogenF36206) used to detect calcium mobilization was sourced by Invitrogen.The assay utilized 384-well, black, optical bottom assay plates (3683)and 384-well clear, non-binding plates (3640) as a compound sourceplate, both from Corning. The neurotensin 1 agonist control (1909) wasobtained from Tocris (Bristol, U.K.).

NTR1 HTS

Primary Screen

The high-content imaging based NTR1 primary screen in 1536-well formatwas utilized to assay the MLSMR library of chemical entities in thefollowing manner. On day one, 4 uL of a cell suspension containing350,000 NTR1-U2OS cells per mL is added to each well of a 1536-wellassay plate. Cells are plated in MEM medium containing 2.5% Fetal BovineSerum, 1% Penicillin/Streptomycin solution, 1% L-Glutamine, 400 ug/mLG418, and 200 ug/mL Zeocin. The assay plates are then incubatedovernight at 37° C., under 5% CO₂. Following the overnight incubation, avolume of 60 nL of the compounds at 2 mM in DMSO (final 20 μM, 1% DMSO)was transferred to columns 5-48 of the assay plates using a LabCyte EchoLiquid Handler. Next, 60 nL of DMSO were dispensed to columns 1-4, whichserved as the positive and neutral control wells. A volume of 2 μL of300 nM neurotensin 1 (FAC=100 nM) peptide dissolved in DPBS was added tothe positive control wells of columns 1 and 2, and 2 μL of DPBS only wastransferred to the neutral control wells of columns 3 and 4 using aKalypsys liquid handler (Kalypsys Systems). The assay plates werecentrifuged on an Eppendorf 5810 centrifuge at 1000 rpm for 1 min toensure even liquid levels in the wells of the assay plates. The assayplates were then returned to the incubator for 1 hour. Following thehour-long incubation at 37° C., the cells in each well were fixed with 4μL of 6% paraformaldehyde added with a Multidrop Combi. The assay plateswere centrifuged as before and incubated at room temperature for 1 hour.On the Kalypsys, plates were then aspirated down to 2.5 μL per well andwashed twice with 11 μL per well of DPBS, followed by a final aspirationto 2.5 μL per well. On the Combi dispenser, 5 μL of 5 ug/mL Hoechst33342 diluted in DPBS was added to each well of assay plates. The plateswere again centrifuged as previously described, sealed, and incubatedfor at least 1 hour prior to being loaded on a PerkinElmer Opera QEHS.

Image acquisition was performed with a 45 plate capacity loader/stackerand the following settings: 40×0.6 NA air objective, acquisition cameraset to 2-by-2 binning for an image size of 688 by 512 pixels,beta-arrestin-GFP acquired using 488 nm laser excitation and 540/75 nmemission filters, DAPI (nuclei) using 365 nm Xenon lamp excitation and450/50 nm emission filters, 3 fields per well. Image analysis wasperformed using the Acapella Spot Detection Algorithm. For analysissettings and the metrics employed in the data analyses, please refer tosupplemental information.

Compounds were selected as hits if they exhibited a percent activity ofgreater than or equal to 40 when compared to the neurotensin 1 controlin the “Ratio of Spot Intensity to Cytoplasmic Intensity” metric.Compounds were excluded from the hit set if the “CellCount” was lessthan or equal to 20 which was indicative of cellular toxicity.

NTR1 Single Concentration Hit Confirmation

Hits from the primary screen were ordered and received from the MLSMR as10 mM solutions in DMSO. The hit confirmation assays were performed inan identical manner as the primary screen with the exception of thesource plate compound concentration, and therefore the volumetransferred to the assay plate to achieve the same concentration as inthe primary screen. A volume of 12.5 nL of test compounds at 10 mM inDMSO (final 20 μM, 0.2% DMSO) was delivered. Compounds were screened inquadruplicate and those with an average activity with regards to the“Ratio of Spot Intensity to Cytoplasmic Intensity” metric of greaterthan or equal to 40% were identified as being “confirmed”.

NTR1 Dose Response

Compounds that were successfully confirmed in quadruplicate at 20 μMwere then run in dose response in the primary assay. As with the singleconcentration hit confirmation, the assay was performed in an identicalmanner as the primary screen with the following modifications. For theinitial hit confirmation in dose response, 40, 20, 10, 5, and 2.5 nL of6 mM and 188 μM test compound in DMSO were transferred from source wellto assay wells to achieve the final assay concentrations ranging from 40to 0.078 μM. Test compound wells and control wells were backfilled withDMSO to achieve a final volume of DMSO of 40 nL or a final assayconcentration of 0.5%. EC₅₀ values for this assay and the following doseresponse assays were calculated in the CBIS database (Cheminnovation)using the same analysis parameters and metrics as in the primary assay.All subsequent dose response assays followed the same basic protocol.

NTR2 Dose Response

The operating procedure used for the NTR1 dose response assay wasadapted to the development of the NTR2 assay which was used to assessreceptor selectivity. The protocol put to use for the NTR2 dose responseassays was identical to that used in the NTR1 dose response experimentswith a few deviations. Firstly, the NTR2-U2OS cell line was used for theassay, but cell densities as well as cell media in the assay remainedthe same. Secondly, because the response of the NTR2 cell line to theneurotensin 1 peptide was low relative to the primary NTR1 cell line, anon-specific, small molecule3-(4-fluorophenyl)-7,8-dimethoxy-5-(4-methylbenzyl)-5H-pyrazolo[4,3-c]quinolinewas used at a saturating concentration of 10 μM to generate a morerobust signal window.

GPR35 Dose Response

The GPR35 dose response assay was used to assess selectivity against anunrelated GPCR. It utilized a very similar protocol to the NTR1 and NTR2dose response assays with a few modifications. The GPR35-U2OS cells wereplated at the same density and in the same media as the other twoassays. Zaprinast was added to control wells in the same volume and inthe same manner as the NTR1 primary assay to yield a final concentrationof 40 μM.

NTR1β-Arrestin Dose Response

On day one of the assay, 5 μL of a cell suspension containing 120,000NTSR1 (NTR1) CHO-K1 cells per mL in OCC2 media is added to each well ofa 1536-well assay plate using a Multidrop Combi. The assay plates arethen incubated for 48 hours at 37° C., under 5% CO₂. Following the twoday incubation, a volume of 20, 10, and 5 nL of 10 and 1.2 mM testcompounds in DMSO were transferred from source wells to test compoundwells in assay plates with a LabCyte Echo to achieve final assayconcentrations ranging from 33 to 1.03 μM for each test sample. Testcompound wells and control wells were backfilled with DMSO to achieve afinal volume of DMSO of 20 nL or a final assay concentration of 0.33%.Next, 1 μL of 120 nM neurotensin 1 peptide (FAC=20 nM) control dilutedin assay media is dispensed with a Multidrop Combi to the positivecontrol wells followed by 1 μL of assay media only to the neutralcontrol and test compound wells. The assay plates were centrifuged on anEppendorf 5810 centrifuge at 1000 rpm for 1 minute. The assay plateswere then incubated in the dark at room temperature for 90 minutes.During the incubation, the detection reagent was prepared according tomanufacturer's instructions. After 90 minutes, 3 μL of the detectionreagent is delivered to all wells of each assay plate. Plates are againcentrifuged as previously described then incubated at room temperaturefor 1 hour before being read on the PerkinElmer using a luminescentprotocol.

NTR1 Ca²⁺ Flux Dose Response

NTSR1 (NTR1) CHO cells are plated in 20 μL of assay media containingHam's F12 supplemented with 10% fetal bovine serum and 0.4 mg/mL G418 ata concentration of 1.0×10⁶ cells per mL into black, 384-well assayplates with clear bottoms using a Multidrop liquid handler. Assay platesare incubated at 37° C. in 5% CO₂. The next day, the assay plates areaspirated to remove growth media and washed once with 20 μL of DPBS. TheDPBS is then aspirated from the assay plate and replaced with 25 μL ofFluo-4 NW calcium dye prepared according to the manufacturer'srecommendations then the plates are incubated for 1 hour at 37° C.Following the incubation in the presence of dye, the assay is run on aMolecular Devices FlexStation-III using 494 excitation and 516 emissionwavelengths set to read for 90 seconds with the addition at 18 secondsof 5 μL of 6× final concentration of test compounds and peptide controldiluted in assay media containing 0.1% BSA and no more than 9% DMSO toyield a maximum final DMSO concentration of 1.5%. Percent activation iscalculated based on the maximum response minus the minimum value overthe time course relative to the neurotensin 1 control peptide at 100 μM.EC₅₀ values were calculated for those compounds tested in 8-point dosedependent response.

Representative biological data is presented in Table 1.

TABLE 1 Ex. Chemical name Structure EC₅₀  1{4-[4-(2-azetidin-1-yl-phenyl)- piperazin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-dimethyl-amine

B  2 {4-[4-(2-azetidin-1-yl-phenyl)- piperazin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-ethyl-methyl- amine

B  3 4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-dimethyl-amine

D  4 {4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-ethyl-methyl- amine

D  5 N-{4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-N,N′,N′- trimethyl-ethane-1,2-diamine

C  6 2-({4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-amino)- ethanol

B  7 {4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-(2-methoxy- ethyl)-methyl-amine

C  8 {4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

B  9 {4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-cyclopropyl-quinazolin-6-yl}-methyl-(2- pyrrolidin-1-yl-ethyl)-amine

D  10 2-({2-cyclopropyl-4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

C  11 {2-cyclopropyl-4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2- methoxy-ethyl)-methyl-amine

C  12 {2-Cyclopropyl-4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

C  13 {2-cyclopropyl-4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2- pyrrolidin-1-yl-ethyl)-amine

C  14 N-{2-cyclopropyl-4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-N,N′,N′- trimethyl-ethane-1,2-diamine

C  15 2-({2-(1-Fluoro-cyclopropyl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

A  16 {2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]- quinazolin-6-yl}-(2-methoxy-ethyl)-methyl-amine

B  17 {2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]- quinazolin-6-yl}-methyl-(2-morpholin-4-yl-ethyl)-amine

B  18 {2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]- quinazolin-6-yl}-dimethyl-amine

B  19 {2-(1-dimethylamino- cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]- quinazolin-6-yl}-dimethyl-amine

D  20 {2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]- quinazolin-6-yl}-methyl-propyl- amine

B  21 {4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-[1-(methyl-propyl-amino)-cyclopropyl]- quinazolin-6-yl}-methyl-propyl- amine

D  22 2-{[4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- methyl-amino}-ethanol

A  23 N-[4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- N,N′,N′-trimethyl-ethane-1,2- diamine

D  24 [4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- methyl-(2-pyrrolidin-1-yl-ethyl)- amine

C  25 2-{[4-[4-(2-dimethylamino- phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6- yl]-methyl-amino}-ethanol

C  26 [4-[4-(2-dimethylamino-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-(2- methoxy-ethyl)-methyl-amine

D  27 [4-[4-(2-dimethylamino-1-vinyl- propenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6- yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

D  28 N-[4-[4-(2-dimethylamino- phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6- yl]-N,N′,N′-trimethyl-ethane-1,2-diamine

D  29 [4-[4-(2-dimethylamino-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- methyl-(2-pyrrolidin-1-yl-ethyl)- amine

D  30 2-{[4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- methyl-amino}-ethanol

C  31 [4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-(2- methoxy-ethyl)-methyl-amine

D  32 [4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- methyl-(2-morpholin-4-yl-ethyl)- amine

D  33 N-(2-methoxyethyl)-4-(4-(2- methoxyphenyl)piperidin-1-yl)-N-methyl-2-(1- methylcyclopropyl)quinazolin-6- amine

C  34 4-(4-(2-methoxyphenyl)piperidin- 1-yl)-N-methyl-2-(1-methylcyclopropyl)-N-(2- morpholinoethyl)quinazolin-6- amine

C  35 N-[4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- N,N′,N′-trimethyl-ethane-1,2- diamine

D  36 [4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- methyl-(2-pyrrolidin-1-yl-ethyl)- amine

D  37 {2-cyclopentyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-dimethyl-amine

D  38 2-({2-cyclopentyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)- ethanol

C  39 {2-cyclopentyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2-methoxy- ethyl)-methyl-amine

D  40 2-cyclopentyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl- amine

D  41 2-cyclopentyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

D  42 {2-cyclobutyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-dimethyl-amine

C or D  43 2-({2-cyclobutyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)- ethanol

B  44 2-cyclobutyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2-methoxy- ethyl)-methyl-amine

C  45 {2-cyclobutyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl- amine

D  46 {2-cyclobutyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

C  47 2-{[4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)- quinazolin-6-yl]-methyl-amino}- ethanol

A  48 [4-(2-methoxy-phenyl)-piperidin- 1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]- methyl-(2-morpholin-4-yl-ethyl)- amine

C  49 2-{[4-[4-(2-dimethylamino- phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)- quinazolin-6-yl]-methyl-amino}- ethanol

B  50 [4-[4-(2-dimethylamino-phenyl)- piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)- quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

D  51 2-{[4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]- methyl-amino}-ethanol

C  52 4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]- methyl-(2-morpholin-4-yl-ethyl)- amine

C  53 {[4-[4-(2-Dimethylamino-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]- methyl-amino}-ethanol

C  54 [4-[4-(2-dimethylamino-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]- methyl-(2-morpholin-4-yl-ethyl)- amine

C  55 2-{[4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)- quinazolin-6-yl]-methyl-amino}- ethanol

C  56 [4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)- quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

C  57 2-{[4-[4-(2-dimethylamino- phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)- quinazolin-6-yl]-methyl-amino}- ethanol

B  58 [4-[4-(2-dimethylamino-phenyl)- piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)- quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

C  59 2-({2-(1-fluoro-cyclobutyl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

A  60 {2-(1-fluoro-cyclobutyl)-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

A  61 2-{[4-[4-(2-dimethylamino- phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclobutyl)-quinazolin-6- yl]-methyl-amino}-ethanol

A  62 [4-[4-(2-dimethylamino-phenyl)- piperidin-1-yl]-2-(1-fluoro-cyclobutyl)-quinazolin-6-yl]- methyl-(2-morpholin-4-yl-ethyl)- amine

B  63 2-{[4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)- quinazolin-6-yl]-methyl-amino}- ethanol

B  64 [4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)- quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)-amine

D  65 2-{[4-[4-(2-Dimethylamino- phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)- quinazolin-6-yl]-methyl-amino}- ethanol

C  66 Preparation of [4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl- cyclobutyl)-quinazolin-6-yl]-methyl-(2-morpholin-4-yl-ethyl)- amine

D  67 [4-[4-(2-dimethylamino-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]- methyl-(2-morpholin-4-yl-ethyl)- amine

D  68 2-{[4-[4-(2-dimethylamino- phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6- yl]-methyl-amino}-ethanol

B  69 [4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]- methyl-(2-morpholin-4-yl-ethyl)- amine

B  70 2-{[4-[4-(2-Methoxy-phenyl)- piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]- methyl-amino}-ethanol

B  71 {2-(1fluoro-cyclopentyl)-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

C  72 2-({2-(1-fluoro-cyclopentyl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

B  73 [4-[4-(2-dimethylamino-phenyl)- piperidin-1-yl]-2-(1-fluoro-cyclopentyl)-quinazolin-6-yl]- methyl-(2-morpholin-4-yl-ethyl)- amine

C  74 {2-cyclopentyl-4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

C  75 2-{[4-[4-(2-dimethylamino- phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclopentyl)-quinazolin-6- yl]-methyl-amino}-ethanol

C  76 1-{2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol

C  77 {2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-6-(4-methoxy-piperidin-1-yl)- quinazoline

C  78 (1-{2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)- dimethyl-amine

D  79 1-{2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol

B  80 2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)- quinazoline

B  81 (R)-1-{2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol, HCl salt

A  82 (S)-1-(2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)pyrrolidin-3-ol

B  83 (R)-2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1- yl)quinazoline, HCl salt

A  84 (S)-2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1- yl)quinazoline

B  85 {2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl- propyl-amine

D  86 {2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-dimethyl- amine

D  87 {2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 6-ylmethyl}-(2-methoxy-ethyl)-methyl-amine

C  88 {2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 6-ylmethyl}-methyl-(2-morpholin-4-yl-ethyl)-amine

D  89 2-({2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylmethyl}-methyl- amino)-ethanol

D  90 ({2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)- acetic acid ethyl ester

D  91 (1-{2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-yl)- dimethyl-amine

C  92 (1-{2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)- ethoxycarbonylmethyl-amino]- aceticacid ethyl ester

D  93 [(1-{2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)- methyl-amino]-acetic acid ethyl ester

D  94 2-{2-Dimethylamino-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-ylamino}-ethanol

B  95 4-(4-(2-methoxyphenyl)piperidin- 1-yl)-N2,N2,N6-trimethyl-N6-propylquinazoline-2,6-diamine

D  96 4-(4-(2-methoxyphenyl)piperidin- 1-yl)-N2,N2-dimethyl-N6,N6-dipropylquinazoline-2,6-diamine

D  97 N2-Cyclobutyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-N6-methyl-N6-propyl-quinazoline-2,6- diamine

D  98 2-((2-(cyclobutylamino)-4-(4-(2- methoxyphenyl)piperidin-1-yl)quinazolin-6- yl)(methyl)amino)ethanol

D  99 2-({2-cyclopropyl-4-[6-(2- methoxy-phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

C 100 {2-cyclopropyl-4-[6-(2-methoxy- phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}-methyl- propyl-amine

C 101 {2-cyclopropyl-4-[6-(2-methoxy- phenyl)-2,6-diaza-spiro[3,3]hept-2-yl]-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

D 102 1-[2-cyclopropyl-6-(methyl- propyl-amino)-quinazolin-4-yl]-4-(2-methoxy-phenyl)-piperidin-2- one

D 103 2-({5-chloro-2-cyclopropyl-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

A 104 {7-chloro-2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl- amine

D 105 {2-cyclopropyl-7-fluoro-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl- amine

C 106 {4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-2-cyclopropyl-7-fluoro-quinazolin-6-yl}-methyl- propyl-amine

D 107 2-({7-chloro-2-cyclopropyl-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

B 108 2-({2-cyclopropyl-4-[4-(4-fluoro- 2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

B 109 2-({2-cyclopropyl-4-[4-(5-fluoro- 2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

B 110 2-({2-cyclopropyl-7-fluoro-4-[4- (4-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

B 111 2-({2-cyclopropyl-7-fluoro-4-[4- (5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

B 112 2-({7-chloro-2-cyclopropyl-4-[4- (4-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

D 113 2-({7-chloro-2-cyclopropyl-4-[4- (5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

C 114 2-({2-cyclopropyl-4-[4-(4-fluoro-2-methoxy-phenyl)-piperidin-1-yl]- 7-methyl-quinazolin-6-yl}-methyl-amino)-ethanol

C 115 2-({2-cyclopropyl-4-[4-(5-fluoro- 2-methoxy-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}- methyl-amino)-ethanol

C 116 2-({2-cyclopropyl-4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}- methyl-amino)-ethanol

B 117 2-({2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl- amino)-ethanol

A 118 2-({7-chloro-2-cyclopropyl-4-[4- (2-dimethylamino-phenyl)-piperidin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

C 119 2-({4-[4-(2-azetidin-1-yl-phenyl)- piperidin-1-yl]-7-chloro-2-cyclopropyl-quinazolin-6-yl}- methyl-amino)-ethanol

C 120 2-({2-cyclopropyl-4-[4-(2- dimethylamino-phenyl)-piperidin-1-yl]-7-fluoro-quinazolin-6-yl}- methyl-amino)-ethanol

A 121 2-({4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-cyclopropyl-7- methyl-quinazolin-6-yl}-methyl-amino)-ethanol

B 122 {2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl-propyl- amine

B 123 {2-cyclopropyl-4-[4-(5-fluoro-2- methoxy-phenyl)-piperidin-1-yl]-7-methyl-quinazolin-6-yl}-methyl- propyl-amine

D 124 2-({2-cyclopropyl-7-fluoro-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

A 125 2-({2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-8-methyl-quinazolin-6-yl}-methyl- amino)-ethanol

A 126 2-({2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-5-methyl-quinazolin-6-yl}-methyl- amino)-ethanol

B 127 2-({2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-8-yl}-methyl-amino)- ethanol

D 128 {2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-8-yl}-methyl-propyl- amine

D 129 {2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-8-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

D 130 2-({8-chloro-2-cyclopropyl-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

A 131 {2-cyclopropyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-5-yl}-methyl-propyl- amine

C 132 2-((2-cyclopropyl-5-fluoro-4-(4-(2- methoxyphenyl)piperidin-1-yl)quinazolin-6- yl)(methyl)amino)ethanol

B 133 2-((2-cyclopropyl-8-fluoro-4-(4-(2- methoxyphenyl)piperidin-1-yl)quinazolin-6- yl)(methyl)amino)ethanol

A 134 2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)-N-methyl-N-(2- morpholinoethyl)pyrido[3,4- d]pyrimidin-6-amine

B 135 2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)-N-methyl-N-propylquinazolin-7- amine

D 136 2-((2-(cyclopropylethynyl)-4-(4-(2- methoxyphenyl)piperidin-1-yl)quinazolin-6- yl)(methyl)amino)ethanol

C 137 2-({2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}- methyl-amino)-ethanol

A 138 2-((2-cyclopropyl-4-(4-(3- methoxythiophen-2-yl)piperidin-1-yl)quinazolin-6- yl)(methyl)amino)ethanol

B 139 2-((4-(4-cyclohexylpiperidin-1-yl)- 2-(1-fluorocyclopropyl)quinazolin-6- yl)(methyl)amino)ethanol

D 140 2-(4-{2-cyclopropyl-6-[(2- hydroxy-ethyl)-methyl-amino]-quinazolin-4-yl}-piperazin-1-yl)- cyclopentanol

D 141 2-{4-[2-cyclopropyl-6-(methyl- propyl-amino)-quinazolin-4-yl]-piperazin-1-yl}-cyclopentanol

D 142 2-(4-{2-cyclopropyl-6-[methyl-(2- morpholin-4-yl-ethyl)-amino]-quinazolin-4-yl}-piperazin-1-yl)- cyclopentanol

D 143 4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-dimethyl-amine

D 144 2-({4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-methyl-amino)- ethanol

C 145 (2-methoxy-ethyl)-{4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-methyl- amine

D 146 {4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-methyl-propyl- amine

D 147 {4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-2-phenyl-quinazolin-6-yl}-methyl-(2- morpholin-4-yl-ethyl)-amine

D 148 {[2-cyclopropyl-4-(5-methoxy-3,4- dihydro-1H-isoquinolin-2-yl)-quinazolin-6-yl]-methyl-amino}- ethanol

D 149 2-{[2-cyclopropyl-4-(4-methoxy- 1,3-dihydro-isoindol-2-yl)-quinazolin-6-yl]-methyl-amino}- ethanol

D 150 2-{[2-cyclopropyl-4-(6-methoxy- 1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-quinazolin-6-yl]-methyl- amino}-ethanol

D 151 2-[(2-cyclopropyl-4-{2-[(2- methoxy-phenyl)-methyl-amino]-cyclopentylamino}-quinazolin-6- yl)-methyl-amino]-ethanol

D 152 2-cyclopropyl-N4-{2-[(2-methoxy- phenyl)-methyl-amino]-cyclopentyl}-N6-methyl-N6- propyl-quinazoline-4,6-diamine

D 153 2-({2-cyclopropyl-4-[3-(2- methoxy-phenylamino)-pyrrolidin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

D 154 2-((2-cyclopropyl-4-((1-(2- methoxyphenyl)pyrrolidin-3-yl)amino)quinazolin-6- yl)(methyl)amino)ethanol

D 155 2-cyclopropyl-N4-(1-(2- methoxyphenyl)pyrrolidin-3-yl)-N6-methyl-N6-propylquinazoline- 4,6-diamine

D 156 Methyl 2-(2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)-6-methylpyrimidin-5-yl)acetate

D 157 2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl- pyrimidin-5-yl}-N,N-dimethyl-acetamide

D 158 2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl- pyrimidin-5-yl}-N-methyl-N-propyl-acetamide

D 159 2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl- pyrimidin-5-yl}-N-(2-hydroxy-ethyl)-N-methyl-acetamide

D 160 2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl- pyrimidin-5-yl}-1-phenyl-ethanone

D 161 {4-cyclopropyl-2-[4-(2-methoxy- phenyl)-piperidin-1-yl]-6-methyl-pyrimidin-5-yl}-acetic acid methyl ester

D 162 2-{4-cyclopropyl-2-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl- pyrimidin-5-yl}-N-methyl-N-propyl-acetamide

D 163 2-{4-cyclopropyl-2-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl- pyrimidin-5-yl}-N-(2-hydroxy-ethyl)-N-methyl-acetamide

D 164 2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-methyl- pyrimidin-5-yl}-N-methyl-N-propyl-acetamide

D 165 2-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrimidin- 5-yl}-N-methyl-N-propyl- acetamide

D 166 2-({2-Cyclopropyl-8-fluoro-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

A 167 2-({2-Cyclopropyl-5-fluoro-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

B 168 2-({2-Cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-5-yl}-methyl-amino)- ethanol

D 169 2-({2-Cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-7-yl}-methyl-amino)- ethanol

C 170 {2-Cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 7-yl}-methyl-propyl-amine

C 171 (1-Fluoro-cyclopropyl)-{7-fluoro- 6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(2-methoxy-phenyl)- piperidin-1-yl]-quinazolin-2-yl}-methanone

A 172 {7-Chloro-6-[(2-hydroxy-ethyl)- methyl-amino]-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 2-yl}-(1-fluoro-cyclopropyl)-methanone

B 173 (S)-1-(2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)pyrrolidin-3-ol

B 174 (S)-2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1- yl)quinazoline

B 175 (R)-1-{2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol

B 176 (R)-2-cyclopropyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)- quinazoline

B 177 (S)-1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin- 1-yl]-quinazolin-6-yl}-pyrrolidin- 3-ol

B 178 (R)-1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin- 1-yl]-quinazolin-6-yl}-pyrrolidin- 3-ol

B 179 ({2-Cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 6-yl}-methyl-amino)-acetic acid

A 180 2-((2-(1-fluorocyclopropyl)-4-(4- (2-methoxyphenyl)piperidin-1-yl)quinazolin-6- yl)(methyl)amino)acetic acid

C 181 2-((8-chloro-2-(1- fluorocyclobutyl)-4-(4-(2-methoxyphenyl)piperidin-1- yl)quinazolin-6- yl)(methyl)amino)ethanol

B 182 3-{8-Chloro-2-(1-fluoro- cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 6-yl}-cyclopentanol

C 183 3-{8-Chloro-2-(1-fluoro- cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 6-yl}-cyclopentanol

C 184 2-({2-Cyclopropyl-4-[4-(2- methoxy-cyclopentyl)-piperazin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

D 185 2-cyclopropyl-4-(4-(2- methoxycyclopentyl)piperazin-1-yl)-N-methyl-N-propylquinazolin- 6-amine

D 186 2-({2-Cyclopropyl-4-[1-(2- methoxy-phenyl)-pyrrolidin-3-ylamino]-quinazolin-6-yl}-methyl- amino)-ethanol

D 187 2-Cyclopropyl-N4-[1-(2-methoxy- phenyl)-pyrrolidin-3-yl]-N6-methyl-N6-propyl-quinazoline-4,6- diamine

D 188 2-{[4-(4-Cyclohexyl-piperidin-1- yl)-2-(1-fluoro-cyclopropyl)-quinazolin-6-yl]-methyl-amino}- ethanol

D 189 2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-cyclohexyl)-piperidin- 1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

D 190 2-({2-Cyclopropyl-4-[4-(3- methoxy-thiophen-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl- amino)-ethanol

C 191 2-({2-Cyclopropylethynyl-4-[4-(2- methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)- ethanol

C 192 2-({2-Ethynyl-4-[4-(2-methoxy- phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol

et 193 2-((2-cyclobutoxy-4-(4-(2- methoxyphenyl)piperidin-1-yl)quinazolin-6- yl)(methyl)amino)ethanol

B 194 2-cyclopropyl-4-(4-(2- methoxyphenyl)piperidin-1-yl)-N-methyl-N-(2- morpholinoethyl)pyrido[3,4- d)pyrimidin-6-amine

B 195 2-({2-(1-Fluoro-cyclopropyl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}- methyl-amino)-ethanol

A 196 1-{2-(1-Fluoro-cyclopropyl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}- pyrrolidin-3-ol

B 197 1-{2-(1-Fluoro-cyclopropvl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}- pyrrolidin-3-ol

B 198 2-({2-(1-Fluoro-cyclobutyl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}- methyl-amino)-ethanol

C 199 1-{2-(1-Fluoro-cyclobutyl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}- pyrrolidin-3-ol

C 200 1-{2-(1-Fluoro-cyclobutyl)-4-[4- (2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}- pyrrolidin-3-ol

C 201 2-({8-Chloro-2-(1-fluoro- cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 6-yl}-methyl-amino)-ethanol

A 202 1-{8-Chloro-2-(1-fluoro- cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 6-yl}-pyrrolidin-3-ol

B 203 1-{8-Chloro-2-(1-fluoro- cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin- 6-yl}-pyrrolidin-3-ol

C 204 2-{[8-Fluoro-4-[4-(3-methoxy- pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6- yl]-methyl-amino}-ethanol

B 205 2-{[4-[4-(3-Methoxy-pyrazin-2- yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]- methyl-amino}-ethanol

B 206 2-{[2-(1-Fluoro-cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H- [2,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

B 207 2-{[2-(1-Fluoro-cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H- [3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

B 208 2-({2-(1-Fluoro-cyclopropyl)-4-[4- (3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol.

B 209 2-({2-(1-Fluoro-cyclopropyl)-4-[4- (3-methoxy-pyridin-2-yl)-piperazin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

C 210 2-{[2-(1-Fluoro-cyclopropyl)-4-(4-methoxy-3′,4′,5′,6′-tetrahydro-2′H- [3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

C 211 2-({2-(1-Fluoro-cyclopropyl)-4-[4- (5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol

D 212 2-{[2-(1-Fluoro-cyclopropyl)-4-(3′-methoxy-3′,4′,5′,6′-tetrahydro-2H- [4,4′]bipyridinyl-1-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

D 213 2-({8-Fluoro-2-(1-fluoro- cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]- quinazolin-6-yl}-methyl-amino)- ethanol

B 214 2-{[8-Fluoro-2-(1-fluoro- cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H- [3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

B 215 2-({8-Fluoro-2-(1-fluoro- cyclopropyl)-4-[4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl]- quinazolin-6-yl}-methyl-amino)- ethanol

B 216 2-{[8-Fluoro-2-(1-fluoro- cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H- [2,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol

C 217 2-({8-Fluoro-2-(1-fluoro- cyclopropyl)-4-[4-(5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]- quinazolin-6-yl}-methyl-amino)- ethanol

D 218 2-({2-(1-Fluoro-cyclopropyl)-4-[4- (4-iodo-2-methoxy-phenyl)-piperazin-1-yl]-quinazolin-6-yl}- methyl-amino)-ethanol.

D 219 2-({2-(1-Fluoromethyl- cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]- quinazolin-6-yl}-methyl-amino)- ethanol

B 221 1-(6-((2- hydroxyethyl)(methyl)amino)-4-(4-(3-methoxypyrazin-2-yl)piperidin- 1-yl)quinazolin-2-yl)cyclobutanol

D 222 (2-(1-Fluoro-cyclopropyl)-4-{4-[2- (2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)- [2-(2-fluoro-ethoxy)-ethyl]-methyl-amine

C 223 {2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]- quinazolin-6-yl}-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine

B 224 2-{1-[6-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}- 2-(1-fluoro-cyclopropyl)-quinazolin-4-yl]-piperidin-4-yl}- phenol

C 225 2-[(2-(1-Fluoro-cyclopropyl)-4-{4- [2-(2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)- methyl-amino]-ethanol

B A is <0.5 uM; B is 0.5-2 uM; C is 2-10 uM; D is >10 uM.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method for treating substance abuse in asubject comprising administering to the subject in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, or solvate, thereof:

wherein, ring A is phenyl, C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, ormonocyclic heteroaryl; A is CH or N; R¹ is halogen, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ ishydrogen, C₁-C₄alkyl, or C₁-C₄haloalkyl; or R¹ is hydrogen, halogen,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂;and R³ and R⁹ are taken together with the intervening atoms to form anoptionally substituted C₂-C₆heterocycloalkyl; each R^(a) isindependently selected from the group consisting of hydrogen, C₁-C₄alkyl, —C(═O)R¹¹, —C(═O)—O—R¹¹, and —S(═O)₂R¹¹, or 2 R^(a) takentogether with the nitrogen to which they are attached form an optionallysubstituted C₂-C₆heterocycloalkyl; L¹ is absent, C₁-C₄alkylene,C₁-C₄alkenylene, C₁-C₄alkynylene, or —N(R^(b))—; R^(b) is hydrogen,C₁-C₄alkyl, C₁-C₄haloalkyl, —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹; R²is hydrogen, halogen, —CN, —OH, —NO₂, optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄alkoxy, optionally substitutedC₁-C₄haloalkyl, optionally substituted C₁-C₄haloalkoxy, optionallysubstituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₆heterocycloalkyl, optionally substituted phenyl, and optionallysubstituted 5- or 6-membered heteroaryl; R⁵ and R⁶ are eachindependently selected from hydrogen, halogen, —OH, and C₁-C₄alkyl, orwhen on the same carbon, R⁵ and R⁶ taken together form an oxo; R⁷ ishydrogen, halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³, —C(═O)—N(R¹²)—R¹³,—NR¹²C(═O)R¹¹, —C(═O)—O—R¹, —O—C(═O)—R¹¹, —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹,—N(R¹²)S(═O)₂R¹¹, —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally substitutedC₁-C₄haloalkyl, optionally substituted C₁-C₄haloalkoxy, optionallysubstituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₆heterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5- or 6-membered heteroaryl; R⁸ is hydrogen, —OH,C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, or—N(R^(a))₂; R⁹ is hydrogen, C₁-C₄alkyl, or C₁-C₄fluoroalkyl; X is —O— or—N(R^(b))—; R¹⁰ is hydrogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)—O—R¹¹,—C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹, or —C(═O)R¹¹; each R¹¹ is independentlyselected from the group consisting of optionally substituted C₁-C₄alkyl,optionally substituted C₁-C₄fluoroalkyl, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,optionally substituted phenyl, and optionally substituted 5- or6-membered heteroaryl; each of R¹² and R¹³ is independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄fluoroalkyl, optionallysubstituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₆heterocycloalkyl, optionally substituted phenyl, and optionallysubstituted 5- or 6-membered heteroaryl; or R¹² and R¹³, when on thesame nitrogen atom, are taken together with the nitrogen atom to whichthey are attached to form an optionally substitutedC₂-C₆heterocycloalkyl; n is 1, 2, or 3; and m is 1, 2, 3, or
 4. 2. Themethod of claim 1, wherein: the substance abused is an amphetamine, anopioid, a cannabinoid, a barbiturate, a benzodiazepine, nicotine,alcohol, a hallucinogen, cocaine, or combinations thereof.
 3. The methodof claim 1, wherein: the substance abused is a psychostimulant.
 4. Themethod of claim 1, wherein: the compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof, has the followingstructure of Formula (Ia), or a pharmaceutically acceptable salt, orsolvate thereof:


5. The method of claim 4, wherein: R¹ is halogen, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ ishydrogen or C₁-C₄alkyl.
 6. The method of claim 4, wherein: R¹ ishydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,C₁-C₄haloalkoxy, or —N(R^(a))₂; and R³ and R⁹ are taken together withthe intervening atoms to form an optionally substitutedC₂-C₆heterocycloalkyl.
 7. The method of claim 1, wherein the compound ofFormula (I), or a pharmaceutically acceptable salt, or solvate thereof,has the following structure of Formula (Ib), or a pharmaceuticallyacceptable salt, or solvate thereof:


8. The method of claim 7, wherein the compound of Formula (Ib), or apharmaceutically acceptable salt, or solvate thereof, has one of thefollowing structures, or a pharmaceutically acceptable salt, or solvatethereof:


9. The method of claim 7, wherein: A is CH; R⁷ is hydrogen, halogen,—CN, —OH, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy;R⁸ is C₁-C₄alkoxy or —N(R^(a))₂; R¹⁰ is hydrogen or C₁-C₄alkyl; m is 1or 2; and n is 1 or
 2. 10. The method of claim 7, wherein: A is N; R⁷ ishydrogen, halogen, —CN, —OH, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, orC₁-C₄haloalkoxy; R⁸ is C₁-C₄alkoxy or —N(R^(a))₂; R¹⁰ is hydrogen orC₁-C₄alkyl; m is 1 or 2; and n is 1 or 2,
 11. A method for treatingsubstance abuse in a subject comprising administering to the subject inneed thereof a therapeutically effective amount of a compound of Formula(VI), or a pharmaceutically acceptable salt, or solvate, thereof:

wherein, ring A is C₃-C₆cycloalkyl, C₂-C₆heterocycloalkyl, or monocyclicheteroaryl; ring B is an optionally substituted hetereocycloalkyl,wherein if ring B is substituted then it is substituted with R⁵ and R⁶;R¹ is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,C₁-C₄haloalkoxy, or —N(R^(a))₂; each R^(a) is independently selectedfrom the group consisting of hydrogen, C₁-C₄ alkyl, —C(═O)R¹¹,—C(═O)—O—R¹¹, and —S(═O)₂R¹¹, or 2 R^(a) taken together with thenitrogen to which they are attached form an optionally substitutedC₂-C₆heterocycloalkyl; L¹ is absent, C₁-C₄alkylene, C₁-C₄alkenylene,C₁-C₄alkynylene, —O—, or —N(R^(b))—; R^(b) is hydrogen, C₁-C₄alkyl,C₁-C₄haloalkyl, —C(═O)—O—R¹¹, —S(═O)₂R¹¹, or —C(═O)R¹¹; R² is hydrogen,halogen, —CN, —OH, —NO₂, optionally substituted C₁-C₄alkyl, optionallysubstituted C₁-C₄alkoxy, optionally substituted C₁-C₄haloalkyl,optionally substituted C₁-C₄haloalkoxy, optionally substitutedC₃-C₆cycloalkyl, optionally substituted C₂-C₆heterocycloalkyl,optionally substituted phenyl, or optionally substituted 5- or6-membered heteroaryl; L² is absent or an optionally substitutedC₁-C₄alkylene; R³ is hydrogen, C₁-C₄alkyl, or C₁-C₄haloalkyl; R⁴ ishydrogen, optionally substituted C₁-C₄ alkyl, —C₁-C₄ alkylene-C(═O)OR¹¹,—C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄ alkylene-N(R^(b))(R¹⁰); R¹⁰ is hydrogen,C₁-C₄alkyl, C₁-C₄fluoroalkyl, —C(═O)—O—R¹¹, —C(═O)N(R¹²)R¹³, —S(═O)₂R¹¹,or —C(═O)R¹¹; or R¹⁰ and R^(b) are taken together with the N atom towhich they are attached to form a C₂-C₆heterocycle; or R³ and R⁴ takentogether with the nitrogen to which they are attached form an optionallysubstituted C₂-C₆heterocycloalkyl; R⁵ and R⁶ are each independentlyselected from hydrogen, halogen, —OH, and C₁-C₄alkyl, or when on thesame carbon, R⁵ and R⁶ taken together form an oxo; R⁷ is hydrogen,halogen, —CN, —OH, —NO₂, —N(R¹²)—R¹³, —C(═O)—N(R¹²)—R¹³, —NR¹²C(═O)R¹¹,—C(═O)—O—R¹¹, —O—C(═O)—R¹¹, —SR¹², —S(═O)R¹¹, —S(═O)₂R¹¹,—N(R¹²)S(═O)₂R¹¹, —S(═O)₂—N(R¹²)—R¹³, —C(═O)R¹¹, optionally substitutedC₁-C₄alkyl, optionally substituted C₁-C₄alkoxy, optionally substitutedC₁-C₄haloalkyl, optionally substituted C₁-C₄haloalkoxy, optionallysubstituted C₃-C₆cycloalkyl, optionally substitutedC₂-C₆heterocycloalkyl, optionally substituted phenyl, or optionallysubstituted 5- or 6-membered heteroaryl; R⁸ is hydrogen, —OH,C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, C₁-C₄fluoroalkoxy, or—N(R^(a))₂; each R¹¹ is independently selected from the group consistingof optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄fluoroalkyl, optionally substituted C₃₋C₆cycloalkyl, optionallysubstituted C₂-C₆heterocycloalkyl, optionally substituted phenyl, andoptionally substituted 5- or 6-membered heteroaryl; each of R¹² and R¹³is independently selected from the group consisting of hydrogen,optionally substituted C₁-C₄alkyl, optionally substitutedC₁-C₄fluoroalkyl, optionally substituted C₃-C₆cycloalkyl, optionallysubstituted C₂-C₆heterocycloalkyl, optionally substituted phenyl, andoptionally substituted 5- or 6-membered heteroaryl; or R¹² and R¹³, whenon the same nitrogen atom, are taken together with the nitrogen atom towhich they are attached to form an optionally substitutedC₂-C₆heterocycloalkyl; and m is 1, 2, 3 or
 4. 12. The method of claim11, wherein: the substance abused is an amphetamine, an opioid, acannabinoid, a barbiturate, a benzodiazepine, nicotine, alcohol, ahallucinogen, cocaine, or combinations thereof.
 13. The method of claim11, wherein: the substance abused is a psychostimulant.
 14. The methodof claim 11, wherein: ring A is monocyclic heteroaryl; R¹ is hydrogen,halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, or —N(R^(a))₂; L¹ is absent; L² isabsent or —CH₂—; R³ is hydrogen or C₁-C₄alkyl; R⁴ is C₁-C₄ alkyl, —C₁-C₄alkylene-OR¹⁰, or —C₁-C₄ alkylene-N(R^(b))(R¹⁰); or R³ and R⁴ takentogether with the nitrogen to which they are attached form an optionallysubstituted C₂-C₅heterocycloalkyl; R⁷ is hydrogen, halogen, —CN, —OH,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy; and m is 1or
 2. 15. The method of claim 11, wherein: ring A is C₃-C₆cycloalkyl; R¹is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, or —N(R^(a))₂; L¹ isabsent; L² is absent or —CH₂—; R³ is hydrogen or C₁-C₄alkyl; R⁴ is C₁-C₄alkyl, —C₁-C₄ alkylene-OR¹⁰, or —C₁-C₄ alkylene-N(R^(b))(R¹⁰); or R³ andR⁴ taken together with the nitrogen to which they are attached form anoptionally substituted C₂-C₅heterocycloalkyl; R⁷ is hydrogen, halogen,—CN, —OH, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, or C₁-C₄haloalkoxy;and m is 1 or
 2. 16. The method of claim 11, wherein: ring B is anN-containing optionally substituted monocyclic heterocycloalkyl.
 17. Themethod of claim 11, wherein: ring B is an N-containing optionallysubstituted bicyclic heterocycloalkyl or an N-containing optionallysubstituted tricyclic heterocycloalkyl.
 18. A method for treatingsubstance abuse in a subject comprising administering to the subject inneed thereof a therapeutically effective amount of a compound that is:2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-(2-methoxy-ethyl)-methyl-amine;{2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-propyl-amine;{4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-[1-(methyl-propyl-amino)-cyclopropyl]-quinazolin-6-yl}-methyl-propyl-amine;2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;N-[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine;2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-(2-methoxy-ethyl)-methyl-amine;N-[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine;2-{[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;[4-[4-(2-azetidin-1-yl-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-(2-methoxy-ethyl)-methyl-amine;N-(2-methoxyethyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)-N-methyl-2-(1-methylcyclopropyl)quinazolin-6-amine;2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;{[4-[4-(2-Dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-({2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(2-Dimethylamino-phenyl)-piperidin-1-yl]-2-(1-trifluoromethyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(2-Methoxy-phenyl)-piperidin-1-yl]-2-(1-methyl-cyclobutyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-({2-(1-fluoro-cyclopentyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-{[4-[4-(2-dimethylamino-phenyl)-piperidin-1-yl]-2-(1-fluoro-cyclopentyl)-quinazolin-6-yl]-methyl-amino}-ethanol;1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-ol;{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(4-methoxy-piperidin-1-yl)-quinazoline;(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-piperidin-4-yl)-dimethyl-amine;1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)-quinazoline;(R)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;(S)-1-(2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)pyrrolidin-3-ol;(R)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline;(S)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline;[(1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl)}-piperidin-4-yl)-methyl-amino]-aceticacid ethyl ester;4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2,N6-trimethyl-N6-propylquinazoline-2,6-diamine;4-(4-(2-methoxyphenyl)piperidin-1-yl)-N2,N2-dimethyl-N6,N6-dipropylquinazoline-2,6-diamine;N2-Cyclobutyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-N6-methyl-N6-propyl-quinazoline-2,6-diamine;2-((2-(cyclobutylamino)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol;2-({2-cyclopropyl-4-[6-(2-methoxy-phenyl)-2,6-diaza-spiro[3.3]hept-2-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-((2-cyclopropyl-4-(4-(3-methoxythiophen-2-yl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol;2-((4-(4-cyclohexylpiperidin-1-yl)-2-(1-fluorocyclopropyl)quinazolin-6-yl)(methyl)amino)ethanol;2-(4-{2-cyclopropyl-6-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-4-yl}-piperazin-1-yl)-cyclopentanol;2-{4-[2-cyclopropyl-6-(methyl-propyl-amino)-quinazolin-4-yl]-piperazin-1-yl}-cyclopentanol;2-(4-{2-cyclopropyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-quinazolin-4-yl}-piperazin-1-yl)-cyclopentanol;(1-Fluoro-cyclopropyl)-{7-fluoro-6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-2-yl}-methanone;{7-Chloro-6-[(2-hydroxy-ethyl)-methyl-amino]-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-2-yl}-(1-fluoro-cyclopropyl)-methanone;(S)-1-(2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)pyrrolidin-3-ol;(S)-2-cyclopropyl-4-(4-(2-methoxyphenyl)piperidin-1-yl)-6-(3-methoxypyrrolidin-1-yl)quinazoline;(R)-1-{2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl})-pyrrolidin-3-ol;(R)-2-cyclopropyl-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-6-(3-methoxy-pyrrolidin-1-yl)-quinazoline;(S)-1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;(R)-1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;2-((2-(1-fluorocyclopropyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)aceticacid;2-((8-chloro-2-(1-fluorocyclobutyl)-4-(4-(2-methoxyphenyl)piperidin-1-yl)quinazolin-6-yl)(methyl)amino)ethanol;3-{8-Chloro-2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl)}-cyclopentanol;3-{8-Chloro-2-(1-fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl)}-cyclopentanol;2-({2-Cyclopropyl-4-[4-(2-methoxy-cyclopentyl)-piperazin-1-yl]-quinazolin-6-yl)}-methyl-amino)-ethanol;2-cyclopropyl-4-(4-(2-methoxycyclopentyl)piperazin-1-yl)-N-methyl-N-propylquinazolin-6-amine2-{[4-(4-Cyclohexyl-piperidin-1-yl)-2-(1-fluoro-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-cyclohexyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-({2-Cyclopropyl-4-[4-(3-methoxy-thiophen-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-({2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol;1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol;1-{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol;2-({2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-methyl-amino)-ethanol;1-{2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol;1-{2-(1-Fluoro-cyclobutyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-pyrido[3,4-d]pyrimidin-6-yl}-pyrrolidin-3-ol;2-({8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;1-{8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;1-{8-Chloro-2-(1-fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-pyrrolidin-3-ol;2-{[8-Fluoro-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[4-[4-(3-Methoxy-pyrazin-2-yl)-piperidin-1-yl]-2-(1-methyl-cyclopropyl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[2-(1-Fluoro-cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-{[2-(1-Fluoro-cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-({2-(1-Fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-({2-(1-Fluoro-cyclopropyl)-4-[4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-{[2-(1-Fluoro-cyclopropyl)-4-(4-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-({2-(1-Fluoro-cyclopropyl)-4-[4-(5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-{[2-(1-Fluoro-cyclopropyl)-4-(3′-methoxy-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-{[8-Fluoro-2-(1-fluoro-cyclopropyl)-4-(2-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(3-methoxy-pyridin-2-yl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-{[8-Fluoro-2-(1-fluoro-cyclopropyl)-4-(3-methoxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-quinazolin-6-yl]-methyl-amino}-ethanol;2-({8-Fluoro-2-(1-fluoro-cyclopropyl)-4-[4-(5-methoxy-pyrimidin-4-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-({2-(1-Fluoro-cyclopropyl)-4-[4-(4-iodo-2-methoxy-phenyl)-piperazin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-({2-(1-Fluoromethyl-cyclopropyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;2-({2-(1-Fluoro-cyclobutyl)-4-[4-(3-methoxy-pyrazin-2-yl)-piperidin-1-yl]-quinazolin-6-yl}-methyl-amino)-ethanol;1-(6-((2-hydroxyethyl)(methyl)amino)-4-(4-(3-methoxypyrazin-2-yl)piperidin-1-yl)quinazolin-2-yl)cyclobutanol;(2-(1-Fluoro-cyclopropyl)-4-{4-[2-(2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine;{2-(1-Fluoro-cyclopropyl)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-quinazolin-6-yl}-[2-(2-fluoro-ethoxy)-ethyl]-methyl-amine;2-{1-[6-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-methyl-amino}-2-(1-fluoro-cyclopropyl)-quinazolin-4-yl]-piperidin-4-yl}-phenol;or2-[(2-(1-Fluoro-cyclopropyl)-4-{4-[2-(2-fluoro-ethoxy)-phenyl]-piperidin-1-yl}-quinazolin-6-yl)-methyl-amino]-ethanol;or a pharmaceutically acceptable salt, or solvate thereof.
 19. Themethod of claim 18, wherein: the substance abused is an amphetamine, anopioid, a cannabinoid, a barbiturate, a benzodiazepine, nicotine,alcohol, a hallucinogen, cocaine, or combinations thereof.
 20. Themethod of claim 18, wherein: the substance abused is a psychostimulant.